Swallowable drug delivery device and method of delivery

ABSTRACT

Embodiments of the invention provide swallowable devices, preparations and methods for delivering drugs and other therapeutic agents within the GI tract. Some embodiments provide a swallowable device such as a capsule for delivering drugs into the intestinal wall or other GI lumen. The device comprises a capsule sized to be swallowed and pass through the intestinal tract. The capsule can include at least one guide tube, one or more tissue penetrating members positioned in the guide tube, a delivery member, an actuating mechanism and a release element. The release element degrades upon exposure to various conditions in the intestine so as to release and actuate the actuating mechanism. Embodiments of the invention are particularly useful for the delivery of drugs which are poorly absorbed, tolerated and/or degraded within the GI tract.

CROSS-REFERENCES TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.14/507,579, filed Oct. 6, 2014, now U.S. Pat. No. 10,039,908, which is acontinuation of U.S. patent application Ser. No. 13/970,446, filed Aug.19, 2013, now U.S. Pat. No. 8,852,151 which is a divisional of U.S.patent application Ser. No. 12/978,301, filed Dec. 23, 2010, now U.S.Pat. No. 8,562,589, which claims the benefit of priority to U.S.Provisional Application Nos. 61/339,941, filed Mar. 10, 2010,61/284,766, filed Dec. 24, 2009, 61/340,331, filed Mar. 15, 2010, and61/395,304, filed May 10, 2010, all of which are incorporated herein byreference in their entirety.

This application is also related to U.S. application Ser. No.12/978,301, filed Dec. 23, 2010, entitled “Swallowable Drug DeliveryDevice and Method of Delivery”; and Ser. No. 12/978,164, filed Dec. 23,2010, entitled, “Therapeutic Agent Preparations for Delivery into aLumen of the Intestinal Tract Using a Swallowable Drug Delivery Device”;all of which are fully incorporated by reference herein for allpurposes.

BACKGROUND OF THE INVENTION 1. Field of the Invention

Embodiments of the invention relate to swallowable drug deliverydevices. More specifically, embodiments of the invention relate toswallowable drug delivery devices for delivering drugs to the smallintestine.

While there has been an increasing development of new drugs in recentyears for the treatment of a variety of diseases, many have limitedapplication because they cannot be given orally. This is due to a numberof reasons including: poor oral toleration with complications includinggastric irritation and bleeding; breakdown/degradation of the drugcompounds in the stomach; and poor, slow or erratic absorption of thedrug. Conventional alternative drug delivery methods such as intravenousand intramuscular delivery have a number of drawbacks including pain andrisk of infection from a needle stick, requirements for the use ofsterile technique and the requirement and associated risks ofmaintaining an IV line in a patient for an extended period of time.While other drug delivery approaches have been employed such asimplantable drug delivery pumps, these approaches require thesemi-permanent implantation of a device and can still have many of thelimitations of IV delivery. Thus, there is a need for an improved methodfor delivery of drugs and other therapeutic agents.

BRIEF SUMMARY OF THE INVENTION

Embodiments of the invention provide devices, systems, kits and methodsfor delivering drugs and other therapeutic agents to various locationsin the body. Many embodiments provide a swallowable device fordelivering drugs and other therapeutic agents within theGastrointestinal (GI) tract. Particular embodiments provide aswallowable device such as a capsule for delivering drugs and othertherapeutic agents into the wall of the small intestine, large intestineor other GI organ wall. Embodiments of the invention are particularlyuseful for the delivery of drugs and other therapeutic agents which arepoorly absorbed, poorly tolerated and/or chemically degraded (e.g.breakdown of the chemical structure of the molecule) within the GI tract(e.g. the digestive enzymes and acids in the stomach). Further,embodiments of the invention can be used to deliver drugs which werepreviously only capable of or preferably delivered by intravenous orother form of parenteral administration (e.g., intramuscular, etc).Additionally, embodiments of the invention are useful for achievingrapid release of a drug into the blood stream via oral delivery.

Embodiments of the invention provide devices, systems, kits and methodsfor delivering drugs and other therapeutic agents to various locationsin the body. Many embodiments provide a swallowable device fordelivering drugs and other therapeutic agents within theGastrointestinal (GI) tract. Particular embodiments provide aswallowable device such as a capsule for delivering drugs and othertherapeutic agents into the wall of the small intestine or other GIorgan wall. Embodiments of the invention are particularly useful for thedelivery of drugs and other therapeutic agents which are poorlyabsorbed, poorly tolerated and/or degraded within the GI tract. Further,embodiments of the invention can be used to deliver drugs which werepreviously only capable of or preferably delivered by intravenous orother form of parenteral administration (e.g., intramuscular, etc).

In one aspect, the invention provides a swallowable device fordelivering drugs or other therapeutic agent into the wall of the smallor large intestine. The device comprises a capsule sized to be swallowedand pass through the intestinal tract. The capsule includes an interiorvolume and can be fabricated from various biocompatible polymers knownin the art including various biodegradable polymers. The capsule caninclude at least one guide tube, one or more tissue penetrating memberspositioned in the at least one guide tube, a delivery member and anactuating mechanism. Alternatively, the tissue penetrating member can bepositioned in the capsule without a guide tube. The tissue penetratingmember will typically comprise a hollow needle or other like structureand will have a lumen or other compartment and a tissue penetrating endfor penetrating a selectable depth into the intestinal wall. In variousembodiments, the device can include a second and a third tissuepenetrating member with additional numbers contemplated. Each tissuepenetrating member can include the same or a different drug. Inpreferred embodiments having multiple tissue penetrating members, thetissue penetrating members can be symmetrically distributed around theperimeter of the capsule so as to anchor the capsule onto the intestinalwall during delivery of drug. In some embodiments, all or a portion ofthe tissue penetrating member (e.g., the tissue penetrating end) can befabricated from the drug itself. In these and related embodiments, thedrug can have a needle or dart-like structure (with or without barbs)configured to penetrate and be retained in the intestinal wall.

The tissue penetrating member can be fabricated from variousbiodegradable materials (e.g., PGLA) so as to degrade within the smallintestine and thus provide a fail-safe mechanism for detaching thetissue penetrating member from the intestinal wall should this componentbecome retained in the intestinal wall. Additionally, in theses andrelated embodiments, selectable portions of the capsule can befabricated from such biodegradable materials so as to allow the entiredevice to controllably degrade into smaller pieces. Such embodimentsfacilitate passage and excretion of the devices through GI tract. Inparticular embodiments, the capsule can include seams of biodegradablematerial which controllably degrade to produce capsule pieces of aselectable size and shape to facilitate passage through the GI tract.The seams can be pre-stressed, perforated or otherwise treated toaccelerate degradation. The concept of using biodegradable seams toproduce controlled degradation of a swallowable device in the GI tractcan also be applied to other swallowable devices such as swallowablecameras to facilitate passage through the GI tract and reduce thelikelihood of a device becoming stuck in the GI tract.

The delivery member is configured to advance the drug from the capsulethrough the tissue penetrating member lumen and into the intestinalwall. Typically, at least a portion of the delivery member isadvanceable within the tissue penetrating member lumen. The deliverymember can have a piston or like structure sized to fit within thedelivery member lumen. The distal end of the delivery member (the endwhich is advanced into tissue) can have a plunger element which advancesthe drug within tissue penetrating member lumen and also forms a sealwith the lumen. The plunger element can be integral or attached to thedelivery member. Preferably, the delivery member is configured to travela fixed distance within the needle lumen so as to deliver a fixed ormeter dose of drug into the intestinal wall. This can be achieved by oneor more of the selection of the diameter of the delivery member (e.g.,the diameter can be distally tapered), the diameter of the tissuepenetrating member (which can be narrowed at its distal end), use of astop, and/or the actuating mechanism. For embodiments of the devicehaving a tissue penetrating member fabricated from drug (e.g., a drugdart), the delivery member is adapted to advance the dart out of thecapsule and into tissue.

The delivery member and tissue penetrating member can be configured forthe delivery of liquid, semi-liquid or solid forms of drug or all three.Solid forms of drug can include both powder or pellet. Semi liquid caninclude a slurry or paste. The drug can be contained within a cavity ofthe capsule, or in the case of the liquid or semi-liquid, within anenclosed reservoir. In some embodiments, the capsule can include a firstsecond, or a third drug (or more). Such drugs can be contained withinthe tissue penetrating member lumen (in the case of solids or powder) orin separate reservoirs within the capsule body.

The actuating mechanism can be coupled to at least one of the tissuepenetrating member or the delivery member. The actuating mechanism isconfigured to advance the tissue penetrating member a selectabledistance into the intestinal wall as well as advance the delivery memberto deliver the drug and then withdraw the tissue penetrating member fromthe intestinal wall. In some embodiments, e.g., where the tissuepenetrating member is itself the drug, the actuating mechanism isconfigured to leave the tissue penetrating member within the intestinalwall. In various embodiments, the actuating mechanism can comprise apreloaded spring mechanism which is configured to be released by therelease element. Suitable springs can include both coil (includingconical shaped springs) and leaf springs with other spring structuresalso contemplated. In particular embodiments, the spring can be coneshaped to reduce the length of the spring in the compressed state evento the point where the compressed length of the spring is about thethickness of several coils (e.g., two or three) or only one coil.

In particular embodiments the actuating mechanism comprises a spring, afirst motion converter, and a second motion converter and a trackmember. The release element is coupled to the spring to retain thespring in a compressed state such that degradation of the releaseelement releases the spring. The first motion converter is configured toconvert motion of the spring to advance and withdraw the tissuepenetrating element in and out of tissue. The second motion converter isconfigured to convert motion of the spring to advance the deliverymember into the tissue penetrating member lumen. The motion convertersare pushed by the spring and ride along a rod or other track memberwhich serves to guide the path of the converters. They engage the tissuepenetrating member and/or delivery member (directly or indirectly) toproduce the desired motion. They are desirably configured to convertmotion of the spring along its longitudinal axis into orthogonal motionof the tissue penetrating member and/or delivery member thoughconversion in other directions is also contemplated. The motionconverters can have a wedge, trapezoidal or curved shape with othershapes also contemplated. In particular embodiments, the first motionconverter can have a trapezoidal shape and include a slot which engagesa pin on the tissue penetrating member that rides in the slot. The slotcan have a trapezoidal shape that mirrors or otherwise corresponds tothe overall shape of the converter and serves to push the tissuepenetrating member during the upslope portion of the trapezoid and thenpull it back during the down slope portion. In one variation, one orboth of the motion converters can comprise a cam or cam like devicewhich is turned by the spring and engages the tissue penetrating and/ordelivery member.

In other variations, the actuating mechanism can also comprise anelectro-mechanical device/mechanism such as a solenoid, or apiezoelectric device. In one embodiment, the piezoelectric device cancomprise a shaped piezoelectric element which has a non-deployed anddeployed state. This element can be configured to go into the deployedstate upon the application of a voltage and then return to thenon-deployed state upon the removal of the voltage. This and relatedembodiments allow for a reciprocating motion of the actuating mechanismso as to both advance the tissue penetrating member and then withdrawit.

The release element is coupled to at least one of the actuatingmechanism or a spring coupled to the actuating mechanism. In particularembodiments, the release element is coupled to a spring positionedwithin the capsule so as to retain the spring in compressed state.Degradation of the release element releases the spring to actuate theactuation mechanism. In many embodiments, the release element comprisesa material configured to degrade upon exposure to chemical conditions inthe small or large intestine such as pH. Typically, the release elementis configured to degrade upon exposure to a selected pH in the smallintestine, e.g., 7.0. 7.1, 7.2, 7.3, 7.4, 8.0 or greater. However, itcan also be configured to degrade in response to other conditions in thesmall intestine. In particular embodiments, the release element can beconfigured to degrade in response to particular chemical conditions inthe fluids in the small intestine such as those which occur afteringestion of a meal (e.g., a meal high in fats or proteins).

Biodegradation of the release element from one or more conditions in thesmall intestine (or other location in the GI tract) can be achieved byselection of the materials for the release element, the amount of crosslinking of those materials as well as the thickness and other dimensionsof the release elements. Lesser amounts of cross linking and or thinnerdimensions can increase the rate of degradation and visa versa. Suitablematerials for the release element can comprise biodegradable materialssuch as various enteric materials which are configured to degrade uponexposure to the higher pH or other condition in the small intestine. Theenteric materials can be copolymerized or otherwise mixed with one ormore polymers to obtain a number of particular material properties inaddition to biodegradation. Such properties can include withoutlimitation stiffness, strength, flexibility and hardness.

In particular embodiments, the release element can comprise a film orplug that fits over or otherwise blocks the guide tube and retains thetissue penetrating member inside the guide tube and/or capsule. In theseand related embodiments, the tissue penetrating member is coupled to aspring loaded actuating mechanism such that when the release element isdegraded sufficiently, it releases the tissue penetrating member whichthen springs out of the guide tube to penetrate into the intestinalwall. In other embodiments, the release element can be shaped tofunction as a latch which holds the tissue penetrating element in place.In these and related embodiments, the release element can be located onthe exterior or the interior of the capsule. In the interiorembodiments, the capsule and guide tubes are configured to allow for theingress of intestinal fluids into the capsule interior to allow for thedegradation of the release element.

In some embodiments, the actuating mechanism can be actuated by means ofa sensor, such as a pH or other chemical sensor which detects thepresence of the capsule in the small intestine and sends a signal to theactuating mechanism (or to an electronic controller coupled to theactuating mechanism to actuate the mechanism). Embodiments of a pHsensor can comprise an electrode-based sensor or it can be amechanically-based sensor such as a polymer which shrinks or expandsupon exposure to the pH or other chemical conditions in the smallintestine. In related embodiments, an expandable/contractable sensor canalso comprise the actuating mechanism itself by using the mechanicalmotion from the expansion or contraction of the sensor.

According to another embodiment for detecting that the device is in thesmall intestine (or other location in the GI tract), the sensor cancomprise a strain gauge or other pressure/force sensor for detecting thenumber of peristaltic contractions that the capsule is being subject towithin a particular location in the intestinal tract. In theseembodiments, the capsule is desirably sized to be gripped by the smallintestine during a peristaltic contraction). Different locations withinthe GI tract have different number of peristaltic contractions. Thesmall intestine has between 12 to 9 contractions per minute with thefrequency decreasing down the length of the intestine. Thus, accordingto one or more embodiments detection of the number of peristalticcontractions can be used to not only determine if the capsule is in thesmall intestine but the relative location within the intestine as well.

As an alternative or supplement to internally activated drug delivery,in some embodiments, the user may externally activate the actuatingmechanism to deliver drug by means of RF, magnetic or other wirelesssignaling means known in the art. In these and related embodiments, theuser can use a handheld device (e.g., a hand held RF device) which notonly includes signaling means, but also means for informing the userwhen the device is in the small intestine or other location in the GItract. The later embodiment can be implemented by including an RFtransmitter on the swallowable device to signal to the user when thedevice is in the small intestine or other in the GI tract location(e.g., by signaling an input from the sensor). The same handheld devicecan also be configured to alter the user when the actuating mechanismhas been activated and the selected drug(s) delivered. In this way, theuser is provided confirmation that the drug has been delivered. Thisallows the user to take other appropriate drugs/therapeutic agents aswell as make other related decisions (e.g., for diabetics to eat a mealor not and what foods should be eaten). The handheld device can also beconfigured to send a signal to the swallowable device to over-ride theactuating mechanism and so prevent, delay or accelerate the delivery ofdrug. In use, such embodiments allow the user to intervene to prevent,delay or accelerate the delivery of drug based upon other symptomsand/or patient actions (e.g., eating a meal, deciding to go to sleep,exercise etc).

The user may also externally activate the actuating mechanism at aselected time period after swallowing the capsule. The time period canbe correlated to a typical transit time or range of transit times forfood moving through the user's GI tract to a particular location in thetract such as the small intestine.

Another aspect of the invention provides methods for the delivery ofdrugs into the walls of the GI tract using embodiments of the drugswallowable drug delivery devices. Such methods can be used for thedelivery of therapeutically effective amounts of a variety of drugs andother therapeutic agents. These include a number of large moleculepeptides and proteins which would otherwise require injection due totheir chemical breakdown in the stomach/GI tract e.g., growth hormone,parathyroid hormone, insulin, interferons and other like compounds.Suitable drugs and other therapeutic agents which can be delivered byembodiments of invention include various chemotherapeutic agents (e.g.,interferon), antibiotics, antivirals, insulin and related compounds,glucagon like peptides (e.g., GLP-1, exenatide), parathyroid hormones,growth hormones (e.g., IFG and other growth factors), anti-seizureagents, immune suppression agents and anti parasitic agents such asvarious anti malarial agents. The dosage of the particular drug can betitrated for the patient's weight, age or other parameter.

In various method embodiments, embodiments of the drug swallowable drugdelivery device can be used to deliver a plurality of drugs for thetreatment of multiple conditions or for the treatment of a particularcondition (e.g., protease inhibitors for treatment HIV AIDS). In use,such embodiments allow a patient to forgo the necessity of having totake multiple medications for a particular condition or conditions.Also, they provide a means for facilitating that a regimen of two ormore drugs is delivered and absorbed into the small intestine and thus,the blood stream at about the same time. Due to differences in chemicalmakeup, molecular weight, etc, drugs can be absorbed through theintestinal wall at different rates, resulting in differentpharmacokinetic distribution curves and so reaching the target tissue atdifferent times. Embodiments of the invention address this issue byinjecting the desired drug mixtures at about the same time. This in turnimproves pharmacokinetics and thus, the efficacy of the selected mixtureof drugs.

Embodiments of the invention provide devices, systems, kits and methodsfor delivering drugs and other therapeutic agents to various locationsin the body. Many embodiments provide a swallowable device fordelivering drugs and other therapeutic agents within the GI tract.Particular embodiments provide a swallowable device such as a capsulefor delivering drugs and other therapeutic agents into the wall of thesmall intestine or other GI organ wall. Embodiments of the invention areparticularly useful for the delivery of drugs and other therapeuticagents which are poorly absorbed, poorly tolerated and/or chemicallydegraded (e.g. a breakdown of the chemical structure of the molecule)within the GI tract (e.g., by the digestive enzymes and acids in thestomach). Further, embodiments of the invention can be used to deliverdrugs which were previously only capable of or preferably delivered byintravenous or other form of parenteral administration (e.g.,intramuscular, etc).

In one aspect, the invention provides a swallowable device fordelivering drugs or other therapeutic agent into the wall of the smallor large intestine. The device comprises a capsule sized to be swallowedand pass through the intestinal tract. The capsule includes an interiorvolume and can be fabricated from various biocompatible polymers knownin the art including various biodegradable polymers. The capsuleincludes at least one guide tube, one or more tissue penetrating memberspositioned in the at least one guide tube, a delivery member and anactuating mechanism. The tissue penetrating member will typicallycomprise a hollow needle or other like structure and will have a lumenand a tissue penetrating end for penetrating a selectable depth into theintestinal wall. In various embodiments, the device can include a secondand a third tissue penetrating member with additional numberscontemplated. Each tissue penetrating member can include the same or adifferent drug. In preferred embodiments having multiple tissuepenetrating members, the tissue penetrating members can be symmetricallydistributed around the perimeter of the capsule so as to anchor thecapsule onto the intestinal wall during delivery of drug. In someembodiments, all or a portion of the tissue penetrating member (e.g.,the tissue penetrating end) can be fabricated from the drug itself. Inthese and related embodiments, the drug can have a needle or dart-likestructure (with or without barbs) configured to penetrate and beretained in the intestinal wall.

The tissue penetrating member can be fabricated from variousbiodegradable materials (e.g., PGLA) so as to degrade within the smallintestine and thus provide a fail-safe mechanism for detaching thetissue penetrating member from the intestinal wall should this componentbecome retained in the intestinal wall. Additionally, in theses andrelated embodiments, selectable portions of the capsule can befabricated from such biodegradable materials so as to allow the entiredevice to controllably degrade into smaller pieces. Such embodimentsfacilitate passage and excretion of the devices through GI tract. Inparticular embodiments, the capsule can include seams of biodegradablematerial which controllably degrade to produce capsule pieces of aselectable size and shape to facilitate passage through the GI tract.The seams can be pre-stressed, perforated or otherwise treated toaccelerate degradation. The concept of using biodegradable seams toproduce controlled degradation of a swallowable device in the GI tractcan also be applied to other swallowable devices such as swallowablecameras to facilitate passage through the GI tract and reduce thelikelihood of a device becoming stuck in the GI tract.

The delivery member is configured to advance the drug from the capsulethrough the tissue penetrating member lumen and into the intestinal wallsuch as the wall of the small intestine. Typically, at least a portionof the delivery member is advanceable within the tissue penetratingmember lumen. The delivery member can have a piston or like structuresized to fit within the delivery member lumen. The distal end of thedelivery member (the end which is advanced into tissue) can have aplunger element which advances the drug within tissue penetrating memberlumen and also forms a seal with the lumen. The plunger element can beintegral or attached to the delivery member. Preferably, the deliverymember is configured to travel a fixed distance within the needle lumenso as to deliver a fixed or metered dose of drug into the intestinalwall. This can be achieved by one or more of the selection of thediameter of the delivery member (e.g., the diameter can be distallytapered), the diameter of the tissue penetrating member (which can benarrowed at its distal end), use of a stop, and/or the actuatingmechanism. For embodiments of the device having a tissue penetratingmember fabricated from drug (e.g., a drug dart), the delivery member isadapted to advance the dart out of the capsule and into tissue.

The delivery member and tissue penetrating member can be configured forthe delivery of liquid, semi-liquid or solid forms of drug (or othertherapeutic agent) or all three. Solid forms of drug can include bothpowder or pellet. Semi liquid can include a slurry or paste. The drugcan be contained within a cavity of the capsule, or in the case of theliquid or semi-liquid, within an enclosed reservoir. In someembodiments, the capsule can include a first second, or a third drug (ormore). Such drugs can be contained within the tissue penetrating memberlumen (in the case of solids or powder) or in separate reservoirs withinthe capsule body.

The actuating mechanism can be coupled to at least one of the tissuepenetrating member or the delivery member. The actuating mechanism isconfigured to advance the tissue penetrating member a selectabledistance into the intestinal wall as well as advance the delivery memberto deliver the drug and then withdraw the tissue penetrating member fromthe intestinal wall. In various embodiments, the actuating mechanism cancomprise a preloaded spring mechanism which is configured to be releasedby the release element. Suitable springs can include both coil(including conical shaped springs) and leaf springs with other springstructures also contemplated. In particular embodiments, the spring canbe cone shaped to reduce the length of the spring in the compressedstate even to the point where the compressed length of the spring isabout the thickness of several coils (e.g., two or three) or only onecoil.

In particular embodiments the actuating mechanism comprises a spring, afirst motion converter, and a second motion converter and a trackmember. The release element is coupled to the spring to retain thespring in a compressed state such that degradation of the releaseelement releases the spring. The first motion converter is configured toconvert motion of the spring to advance and withdraw the tissuepenetrating element in and out of tissue. The second motion converter isconfigured to convert motion of the spring to advance the deliverymember into the tissue penetrating member lumen. The motion convertersare pushed by the spring and ride along a rod or other track memberwhich serves to guide the path of the converters. They engage the tissuepenetrating member and/or delivery member (directly or indirectly) toproduce the desired motion. They are desirably configured to convertmotion of the spring along its longitudinal axis into orthogonal motionof the tissue penetrating member and/or delivery member thoughconversion in other directions is also contemplated. The motionconverters can have a wedge, trapezoidal or curved shape with othershapes also contemplated. In particular embodiments, the first motionconverter can have a trapezoidal shape and include a slot which engagesa pin on the tissue penetrating member that rides in the slot. The slotcan have a trapezoidal shape that mirrors or otherwise corresponds tothe overall shape of the converter and serves to push the tissuepenetrating member during the upslope portion of the trapezoid and thenpull it back during the down slope portion. In one variation, one orboth of the motion converters can comprise a cam or cam like devicewhich is turned by the spring and engages the tissue penetrating and/ordelivery member.

In other variations, the actuating mechanism can also comprise anelectro-mechanical device/mechanism such as a solenoid, or apiezo-electric device. In one embodiment, the piezo-electric device cancomprise a shaped piezo-electric element which has a non-deployed anddeployed state. This element can be configured to go into the deployedstate upon the application of a voltage and then return to thenon-deployed state upon the removal of the voltage. This and relatedembodiments allow for a reciprocating motion of the actuating mechanismso as to both advance the tissue penetrating member and then withdrawit.

The release element is coupled to at least one of the actuatingmechanism or a spring coupled to the actuating mechanism. In particularembodiments, the release element is coupled to a spring positionedwithin the capsule so as to retain the spring in a compressed state.Degradation of the release element releases the spring to actuate theactuation mechanism. In many embodiments, the release element comprisesa material configured to degrade upon exposure to chemical conditions inthe small or large intestine such as pH. Typically, the release elementis configured to degrade upon exposure to a selected pH in the smallintestine, e.g., 7.0, 7.1, 7.2, 7.3, 7.4, 8.0 or greater. However, itcan also be configured to degrade in response to other conditions in thesmall intestine. In particular embodiments, the release element can beconfigured to degrade in response to particular chemical conditions inthe fluids in the small intestine such as those which occur afteringestion of a meal (e.g., a meal high in fats or proteins).

Biodegradation of the release element from one or more conditions in thesmall intestine (or other location in the GI tract) can be achieved byselection of the materials for the release element, the amount of crosslinking of those materials as well as the thickness and other dimensionsof the release elements. Lesser amounts of cross linking and or thinnerdimensions can increase the rate of degradation and visa versa. Suitablematerials for the release element can comprise biodegradable materialssuch as various enteric materials which are configured to degrade uponexposure to the higher pH or other condition in the small intestine. Theenteric materials can be copolymerized or otherwise mixed with one ormore polymers to obtain a number of particular material properties inaddition to biodegradation. Such properties can include withoutlimitation stiffness, strength, flexibility and hardness.

In particular embodiments, the release element can comprise a film orplug that fits over or otherwise blocks the guide tube and retains thetissue penetrating member inside the guide tube. In these and relatedembodiments, the tissue penetrating member is coupled to a spring loadedactuating mechanism such that when the release element is degradedsufficiently, it releases the tissue penetrating member which thensprings out of the guide tube to penetrate into the intestinal wall. Inother embodiments, the release element can be shaped to function as alatch which holds the tissue penetrating element in place. In these andrelated embodiments, the release element can be located on the exterioror the interior of the capsule. In the interior embodiments, the capsuleand guide tubes are configured to allow for the ingress of intestinalfluids into the capsule interior to allow for the degradation of therelease element.

In some embodiments, the actuating mechanism can be actuated by means ofa sensor, such as a pH or other chemical sensor which detects thepresence of the capsule in the small intestine and sends a signal to theactuating mechanism (or to an electronic controller coupled to theactuating mechanism to actuate the mechanism). Embodiments of a pHsensor can comprise an electrode-based sensor or it can be amechanically-based sensor such as a polymer which shrinks or expandsupon exposure to the pH or other chemical conditions in the smallintestine. In related embodiments, an expandable/contractable sensor canalso comprise the actuating mechanism itself by using the mechanicalmotion from the expansion or contraction of the sensor.

According to another embodiment for detecting that the device is in thesmall intestine (or other location in the GI tract), the sensor cancomprise a strain gauge or other pressure/force sensor for detecting thenumber of peristaltic contractions that the capsule is being subject towithin a particular location in the intestinal tract. In theseembodiments, the capsule is desirably sized to be gripped by the smallintestine during a peristaltic contraction). Different locations withinthe GI tract have different number of peristaltic contractions. Thesmall intestine has between 12 to 9 contractions per minute with thefrequency decreasing down the length of the intestine. Thus, accordingto one or more embodiments detection of the number of peristalticcontractions can be used to not only determine if the capsule is in thesmall intestine but the relative location within the intestine as well.

As an alternative or supplement to internally activated drug delivery,in some embodiments, the user may externally activate the actuatingmechanism to deliver drug by means of RF, magnetic or other wirelesssignaling means known in the art. In these and related embodiments, theuser can use a handheld device (e.g., a hand held RF device) which notonly includes signaling means, but also means for informing the userwhen the device is in the small intestine or other location in the GItract. The later embodiment can be implemented by including an RFtransmitter on the swallowable device to signal to the user when thedevice is in the small intestine or other location (e.g., by signalingan input from the sensor). The same handheld device can also beconfigured to alter the user when the actuating mechanism has beenactivated and the selected drug(s) delivered. In this way, the user isprovided confirmation that the drug has been delivered. This allows theuser to take other appropriate drugs/therapeutic agents as well as makeother related decisions (e.g., for diabetics to eat a meal or not andwhat foods should be eaten). The handheld device can also be configuredto send a signal to the swallowable device to over-ride the actuatingmechanism and so prevent, delay or accelerate the delivery of drug. Inuse, such embodiments allow the user to intervene to prevent, delay oraccelerate the delivery of drug based upon other symptoms and/or patientactions (e.g., eating a meal, deciding to go to sleep, exercise etc).

The user may also externally activate the actuating mechanism at aselected time period after swallowing the capsule. The time period canbe correlated to a typical transit time or range of transit times forfood moving through the user's GI tract to a particular location in thetract such as the small intestine.

Another aspect of the invention provides therapeutic agent preparationsfor delivery into the wall of the small intestine (or other luminal wallin the intestinal tract) using embodiments of the swallowable devicedescribed herein. The preparation comprises a therapeutically effectivedose of at least one therapeutic agent (e.g., insulin, an anti-seizurecompound, NSAIDs, an antibiotic, etc.). It may comprise a solid, liquidor combination of both and can include one or more pharmaceuticalexcipients. The preparation has a shape and material consistency to becontained in embodiments of the swallowable capsule, delivered from thecapsule into the lumen wall and degrade within the lumen wall to releasethe dose of therapeutic agent. The preparation may also have aselectable surface area to volume ratio so as enhance or otherwisecontrol the rate of degradation of the preparation in the wall of thesmall intestine or other body lumen. In various embodiments, thepreparation can be configured to be coupled to an actuator (such as arelease element (and/or other components coupled to the release element)which has a first configuration in which the preparation is contained inthe capsule and a second configuration in which the preparation isadvanced out of the capsule and into the wall of the small intestine.The dose of the drug or other therapeutic agent in the preparation canbe titrated downward from that which would be required for conventionaloral delivery methods so that potential side effects from the drug canbe reduced.

Typically, though not necessarily, the preparation will be shaped andotherwise configured to be contained in the lumen of a tissuepenetrating member, such as a hollow needle which is configured to beadvanced out of the capsule and into the wall of the small intestine.The preparation itself may comprise a tissue penetrating memberconfigured to be advanced into the wall of the small intestine or otherlumen in the intestinal tract.

Another aspect of the invention provides methods for the delivery ofdrugs and the therapeutic agents into the walls of the GI tract usingembodiments of the swallowable drug delivery devices. Such methods canbe used for the delivery of therapeutically effective amounts of avariety of drugs and other therapeutic agents. These include a number oflarge molecule peptides and proteins which would otherwise requireinjection and/or IV infusion due to chemical degradation by thedigestive fluids in the stomach and lumen of the small intestine. Suchcompounds which can be delivered with various embodiments of theinvention can include without limitation, growth hormone, parathyroidhormone, insulin compounds, antibodies and other gamma globulin proteins(e.g., gamma globulin) interferons and other cytokines, glucagon likepeptides e.g., (GLP-1, exenatide) and other incretins, parathyroidhormones, growth hormones (e.g., IFG and other growth factors),chemotherapeutic agents (doxorubicin) and other like compounds. Otherdrugs and other therapeutic agents which can be delivered by embodimentsof invention include any number of orally delivered agents, antibiotics(vancomycin, penicillin, erythromycin, etc.), antivirals (proteaseinhibitors anti-seizure compounds (furosemide, dilatin), NSIAD's(ibuprofen), immune suppression agents and anti parasitic agents such asvarious anti malarial agents. Many of these compounds can includevarious therapeutic agents which if taken by standard oral deliverymethods would cause deleterious effects in the intestinal tract andelsewhere such as cramping, bleeding, diarrhea and irritable bowel.Because various embodiments of the inventions provide for the drug orother therapeutic agent being injected directly into the smallintestine, these effects can largely be avoided and the dosage of thecompound can be adjusted accordingly (e.g., increased in many cases). Invarious embodiments, the dosage of a particular drug can be titrated forthese considerations as well as the patient's weight, age and conditionto be treated.

In various method embodiments, embodiments of the swallowable drugdelivery device can be used to deliver a plurality of drugs for thetreatment of multiple conditions or for the treatment of a particularcondition (e.g., a mixture of protease inhibitors for treatment HIVAIDS). In use, such embodiments allow a patient to forgo the necessityof having to take multiple medications for a particular condition orconditions. Also, they provide a means for facilitating that a regimenof two or more drugs is delivered and absorbed into the small intestineand thus, the blood stream at about the same time. Due to differences inchemical makeup, molecular weight, etc., drugs can be absorbed throughthe intestinal wall at different rates, resulting in differentpharmacokinetic distribution curves. Embodiments of the inventionaddress this issue by injecting the desired drug mixtures into theintestinal wall at about the same time. This in turn improvespharmacokinetics and thus, the efficacy of the selected mixture ofdrugs.

Further details of these and other embodiments and aspects of theinvention are described more fully below, with reference to the attacheddrawing figures.

Embodiments of the invention provide devices, systems, kits and methodsfor delivering drugs and other therapeutic agents to various locationsin the body. Many embodiments provide a swallowable device fordelivering drugs and other therapeutic agents within theGastrointestinal (GI) tract. Particular embodiments provide aswallowable device such as a capsule for delivering drugs and othertherapeutic agents into the wall of the small intestine, large intestineor other GI organ wall. Embodiments of the invention are particularlyuseful for the delivery of drugs and other therapeutic agents which arepoorly absorbed, poorly tolerated and/or degraded within the GI tract.Further, embodiments of the invention can be used to deliver drugs whichwere previously only capable of or preferably delivered by intravenousor other form of parenteral administration (e.g., intramuscular, etc).Additionally, embodiments of the invention are useful for achievingrapid release of a drug into the blood stream via oral delivery.

In one aspect, the invention provides a swallowable device fordelivering drugs or other therapeutic agent into the wall of the smallor large intestine or other intestinal tract organ. The devise comprisesa capsule sized to be swallowed and pass through the intestinal tract,an expandable member positioned within capsule and a tissue penetratingmember advanceable into the intestinal wall by expansion of theexpandable member. The capsule includes an interior volume and at leastone aperture through which the tissue penetrating member can be advancedinto the intestinal wall. The tissue penetrating member is formed atleast in part from a drug or other therapeutic. The capsule can befabricated from various non-toxic materials including variousbiodegradable polymers. The capsule may also have a enteric othercoating for protecting the capsule from stomach acids while allowing forbiodegradation in the small intestine so as to allow the device todeliver drugs and other therapeutic agents into the wall of the smallintestine responsive to pH or other conditions in the small intestine.

A balloon or other expandable member is disposed within the capsuleinterior volume and coupled to the tissue penetrating member. Theballoon will typically be attached to an interior wall of the capsule ina least a partially non-expanded state and can comprise various noncompliant polymers known in the art such as PET, polyethylene andpolyimide. Desirably, the balloon will be thin walled e.g., less thanabout 0.001 inches. The balloon also will typically include at least afirst and a second portion or compartment which are separated by be aseparation valve or other separation means. A liquid, typically water,can be disposed within the first compartment and at least one reactantdisposed in the second compartment which can be liquid though typicallyis solid. The reactants will typically include at least two reactantsfor example, an acid such as citric acid and a base such as sodiumhydroxide, which can have about a 1:2 ratio. Other reactants includingother acids, e.g., ascetic acid and bases are also contemplated. Whenthe valve or other separation means opens, the reactants mix in theliquid and produce a gas such as carbon dioxide which expands theballoon and advances the tissue penetrating member into the intestinalwall as will be explained more fully herein. In addition to advancingthe tissue penetrating members into tissue, the device can also beconfigured to have the inflated balloon break or otherwise separateapart the capsule into one or more pieces for easier passage through theintestinal tract.

The separation valve can be configured to open in a number of ways andresponsive to a number of conditions. Typically, the separation valvewill be configured to open by having one or more portions degrade inresponse to the higher pH or other conditions found within the smallintestine so that upon degradation, the valve opens. Also, typically,the separation valve will be placed in a central portion of the balloon,though other locations are also contemplated. In particular embodiments,the separation valve can have a beam like structure that is placedwithin the capsule to compress the portion of the balloon between thefirst and second compartments. The beam can be attached at one or bothends to the internal surface of the capsule. In preferred embodiments,the beam is attached to the radial sides of the capsule preferably,using an interference fit so that the beam can be snapped into placeusing pick and place and other like methods known in the manufacturingarts. When the beam degrades, the compressive forces are released. Theseand other embodiments of the valve can include one or more pinchingfeatures such as a ridge which engages a depression or other matingfeature on the internal surface of the capsule to apply additional forceon the balloon wall beneath the pinching feature and redundancy to theseal. In another embodiment, the separation valve can comprise a neckedsection of the expandable member with an overlying pinching collar madefrom biodegradable material. The collar holds the valve closed andreleases the valve when degraded.

The separation valve can be positioned in a variety of locations on orwithin the capsule so as to exposed to and degraded by the intestinalfluids. While at least a portion of the valve may be exposed to thecapsule surface, typically, the valve will be positioned within thecapsule interior where it is exposes to intestinal fluids which enterthrough the at least one aperture or other opening. In these and relatedembodiments, at least a portion of the capsule surface including theportion containing the at least one aperture is desirably coated with aprotective layer, such as an enteric coating which also degrades inresponse to pH or other conditions within the small intestine. Suchcoatings provide a protective seal over the at least one aperture sothat digestive fluids do not enter the capsule interior and start todegrade the separation valve until the capsule has reached the smallintestine. In use, embodiments employing a degradable coating/seal overthe aperture and a degradable valve provide a primary and secondarymeans assuring that balloon does not expand and deploy its tissuepenetrating members until the capsule has reached the small intestine.

As an alternative or additional embodiment, the valve may also beconfigured to open in response to compressive forces applied by aperistaltic contraction within the small intestine. In still anotherapproach, the valve may be a time release valve configured to open aftera certain period of time after an activation step initiated by thepatient such as the pealing of a tab or pressing of a button.

In addition to the release valve, the balloon or other expandable memberwill also typically include a deflation valve which serves to deflatethe expandable member after inflation. The deflation valve can comprisebiodegradable materials which are configured to degrade upon exposure tothe fluids in the small intestine and/or liquid in one of thecompartments of the balloon so as to create an opening or channel forescape of gas within balloon. In one embodiment, the deflation valve cancomprise a biodegradable section positioned on an end portion of theballoon so as to join opposing ends of the balloon wall together. Inthis and related embodiments, when the degradable section degrades fromexposure to the liquid, the balloon wall tears or otherwise comes apartproviding for a high assurance of rapid deflation. Multiple degradablesections can be placed, desirably in the solid reactant portion of theballoon wall to provide an even higher degree of reliability indeflation. For embodiments where the deflation valve is degraded byfluids within the small intestine, degradation of the valve can befacilitated by configuring the inflated balloon to break apart thecapsule into two or more pieces so that large sections of the balloonare directly exposed to degrading fluids within the small intestine.This can be achieved by fabricating the capsule from separate parts(e.g., two halves mechanically fit together) and/or through the use ofseams as is described herein.

Additionally, as further backup for insured deflation, one or morepuncture elements can be attached to the inside surface of the capsulewall such that when the balloon fully deflates it is contacts and ispunctured by the puncture element. In another alternative or additionalembodiment of means for deflation, one or more of the tissue penetratingmembers can be directly coupled to the balloon and configured to tearaway from the balloon when they detach, tearing the balloon wall in theprocess.

The tissue penetrating member in this aspect of the invention can befabricated from various drugs and other therapeutic agents. Typically,the drug or other therapeutic agent will be mixed in with abiodegradable polymer such as PGLA. In such embodiments, the penetratingmember may comprise a substantially heterogeneous mixture of drug andbiodegradable polymer. Alternatively, the penetrating member may includea portion formed substantially from biodegradable and a separate sectionor compartment that is formed from or contains the drug. The penetratingmember can be formed to have a shaft and a needle tip or other pointeddistal tip so as to readily penetrate tissue of the intestinal wall.Once placed in intestinal wall, the tissue penetrating member isdegraded by the interstitial fluids within the wall tissue, the drugdissolves in those fluids and is absorbed into the blood stream. Thepenetrating member will also typically include one or more tissueretaining features such as a barb or hook to retain the penetratingmember within the tissue of the intestinal wall after advancement. Theretaining features can be arranged in various patterns to enhance tissueretention such as two or more barbs symmetrically distributed around themember shaft. The drug can be in solid form and then formed into theshape of the tissue penetrating member using molding or other likemethod or may be in solid or liquid form and then added to thebiodegradable polymer in liquid form with the mixture then formed intothe penetrating member using molding or other forming method known inthe polymer arts. Desirably, embodiments of the tissue penetratingmember comprising a drug and degradable polymer are formed (e.g., cured)at temperatures which do not produce any substantial thermal degradationof the drug including drugs such as various peptides and proteins. Thiscan be achieved through the use of room-temperature curing polymers androom temperature molding and solvent evaporation techniques known in theart. In particular embodiments, the amount of thermally degraded drugwithin the tissue penetrating member is desirably less than about 10% byweight, more preferably less than 5% and still more preferably less than1%. The thermal degradation temperatures for a particular drug are knownor can be determined using methods known in the art and then thistemperature can be used to select and adjust the particular polymerprocessing methods (e.g., molding, curing. solvent evaporation etc.).

The tissue penetrating member is desirably detachably coupled (directlyor indirectly) to the balloon or other expandable member so that afteradvancement of the tissue penetrating member into the intestinal wall,the tissue penetrating member detaches from the balloon. The penetratingmember can be configured to detach as a result of balloon deflationwhere the retaining features hold the penetrating member in tissue asthe balloon deflates and/or the forces exerted on the capsule by aperistaltic contraction of the small intestine. Typically, the tissuepenetrating member will be indirectly coupled to the balloon by anadvancement member comprising a rigid structure attached to the balloonsurface which detachably engages the penetrating member. The advancementmember engages the penetrating member by means of an attachment featuresuch as a pin which fits into a recess or other mating feature of thepenetrating member. The pin and recess can be configured to detach fromthe force of balloon deflation and/or force applied to the capsule byperistaltic contraction. The rigid advancement member can have a largerhorizontal surface area than the penetrating member so as to function asa force concentration element to increase the force per unit areaapplied to the penetrating member from balloon expansion. In someembodiments, the advancement member can be coupled to the balloon via aplatform also described herein as a support member having one surfaceattached to the balloon surface and the other attached to theadvancement member. The support member can be sized to allow forattachment and advancement of multiple advancement and tissuepenetrating members. Additionally, the support member can have a largersurface area than the advancement members/tissue penetrating members soas to have a force concentrating function similar to that describedabove for the advancement member. As an additional or alternativeembodiment, the tissue penetrating member may be directly coupled to theballoon, e.g., by an adhesive. In these and related embodiments thetissue penetrating members may be configured to tear the balloon wallwhen they detach and thus provide a means for balloon deflation.

Multiple tissue penetrating members can be coupled to the balloon orother expandable member and they may have a number of arrangements. Inspecific embodiments, the capsule can include two, three or fourpenetrating members with additional numbers contemplated. Thepenetrating members can carry the same or a different drug. The formerprovides for larger amounts of delivery of a particular drug, the laterallows two or more drugs to be delivered into the intestinal wall atabout the same time. The tissue penetrating members can be placed anddistributed in number of locations and patterns on the balloon surface.In particular embodiments, the penetrating members can be placed onopposite sides of the balloon (e.g., 180 apart with respect to theperimeter of the balloon) so that balloon inflation can place tissuepenetrating members on opposite sides of the intestinal wall lumen. Inpreferred embodiments having multiple tissue penetrating members, thetissue penetrating members can be symmetrically distributed around theperimeter of the capsule so as to anchor the capsule onto the intestinalwall during delivery of drug as well as place the tissue penetratingmembers in multiple locations in the intestinal wall. This not onlyallows for additional amounts of drug to be delivered but also providesfor a more even distribution of the drug within the intestinal wallproviding for faster absorption into the blood stream.

As an additional or alternative embodiment to the use of drug carryingtissue penetrating members, various embodiments of the device can alsoinclude drug reservoirs disposed in the capsule which are compressibleby expansion of the balloon or other expandable member. The reservoirscontain drug or other therapeutic agent in liquid or powder form. Forliquid form, the drug will be dissolved in an aqueous drug solution. Inthese and related embodiments, the reservoirs are fluidically coupled toadvanceable hollow tissue penetrating members such that inflation of theballoon compresses the reservoirs so as to force the drug solutionthrough tissue penetrating member and into the intestinal wall. Multiplereservoirs are contemplated including two, three, four or more. Inparticular embodiments, two reservoirs can be coupled to a hollow tissuepenetrating member with the reservoirs placed about 180 degrees apartwith respect to the lengthwise axis of the penetrating member.Typically, the reservoirs will be fluidically coupled to the hollowpenetrating member by means of a manifold. Suitable manifolds include at-shaped manifold having connectors on either of it lateral ends for thereservoirs a central connector for the hollow tissue penetrating memberand a central lumen or channel going to all connectors. Other shapes andmanifold configurations are also contemplated.

In another aspect, the invention provides a swallowable device fordelivering drugs or other therapeutic agent into the wall of the smallor large intestine comprising a capsule sized to be swallowed and passthrough the intestinal tract wherein the capsule includes at least oneguide tube, one or more tissue penetrating members positioned in the atleast one guide tube, a delivery member and an actuating mechanism. Inthese and related embodiments, the tissue penetrating member willtypically comprise a hollow needle or other like structure and will havea lumen and a tissue penetrating end for penetrating a selectable depthinto the intestinal wall. In various embodiments, the device can includea second and a third tissue penetrating member with additional numberscontemplated. Each tissue penetrating member can include the same or adifferent drug. In preferred embodiments having multiple tissuepenetrating members, the tissue penetrating members can be symmetricallydistributed around the perimeter of the capsule so as to anchor thecapsule onto the intestinal wall during delivery of drug. In someembodiments, all or a portion of the tissue penetrating member (e.g.,the tissue penetrating end) can be fabricated from the drug itself. Inthese and related embodiments, the drug can have a needle or dart-likestructure (with or without barbs) configured to penetrate and beretained in the intestinal wall.

Embodiments of the tissue penetrating member in this aspect of theinvention can be fabricated from various biodegradable materials (e.g.,PGLA) so as to degrade within the small intestine and thus provide afail-safe mechanism for detaching the tissue penetrating member from theintestinal wall should this component become retained in the intestinalwall. Additionally, in theses and related embodiments, selectableportions of the capsule can be fabricated from such biodegradablematerials so as to allow the entire device to controllably degrade intosmaller pieces. Such embodiments facilitate passage and excretion of thedevices through GI tract. In particular embodiments, the capsule caninclude seams of biodegradable material which controllably degrade toproduce capsule pieces of a selectable size and shape to facilitatepassage through the GI tract. The seams can be pre-stressed, perforatedor otherwise treated to accelerate degradation. The seams can also be sotreated so to allow the capsule to be broken apart into smaller piecesby the forces applied from expansion of the balloon or other expandablemember. In other embodiments for producing capsule degradation afterdeployment of the tissue penetrating members, the capsule can becomprise two halves or other fractional sections which are mechanicallyfit together, e.g., by a snap fit and thus readily separated by theforces applied from balloon inflation.

The delivery member is configured to advance the drug from the capsulethrough the tissue penetrating member lumen and into the intestinalwall. Typically, at least a portion of the delivery member isadvanceable within the tissue penetrating member lumen. The deliverymember can have a piston or like structure sized to fit within thedelivery member lumen. The distal end of the delivery member (the endwhich is advanced into tissue) can have a plunger element which advancesthe drug within tissue penetrating member lumen and also forms a sealwith the lumen. The plunger element can be integral or attached to thedelivery member. Preferably, the delivery member is configured to travela fixed distance within the needle lumen so as to deliver a fixed ormetered dose of drug into the intestinal wall. This can be achieved byone or more of the selection of the diameter of the delivery member(e.g., the diameter can be distally tapered), the diameter of the tissuepenetrating member (which can be narrowed at its distal end), use of astop, and/or the actuating mechanism. For embodiments of the devicehaving a tissue penetrating member fabricated from a drug (e.g., a drugdart), the delivery member is adapted to advance the tissue penetratingmember out of the capsule and into tissue.

The delivery member and tissue penetrating member can be configured forthe delivery of liquid, semi-liquid or solid forms of drug or all three.Solid forms of drug can include both powder or pellet. Semi liquid caninclude a slurry or paste. The drug can be contained within a cavity ofthe capsule, or in the case of the liquid or semi-liquid, within anenclosed reservoir. In some embodiments, the capsule can include a firstsecond, or a third drug (or more). Such drugs can be contained withinthe tissue penetrating member lumen (in the case of solids or powder) orin separate reservoirs within the capsule body.

The actuating mechanism can be coupled to at least one of the tissuepenetrating member or the delivery member. The actuating mechanism isconfigured to advance the tissue penetrating member a selectabledistance into the intestinal wall as well as advance the delivery memberto deliver the drug and then withdraw the tissue penetrating member fromthe intestinal wall. In various embodiments, the actuating mechanism cancomprise a preloaded spring mechanism which is configured to be releasedby the release element. Suitable springs can include both coil(including conical shaped springs) and leaf springs with other springstructures also contemplated. In particular embodiments, the spring canbe cone shaped to reduce the length of the spring in the compressedstate even to the point where the compressed length of the spring isabout the thickness of several coils (e.g., two or three) or only onecoil.

In particular embodiments, the actuating mechanism comprises a spring, afirst motion converter, and a second motion converter and a trackmember. The release element is coupled to the spring to retain thespring in a compressed state such that degradation of the releaseelement releases the spring. The first motion converter is configured toconvert motion of the spring to advance and withdraw the tissuepenetrating element in and out of tissue. The second motion converter isconfigured to convert motion of the spring to advance the deliverymember into the tissue penetrating member lumen. The motion convertersare pushed by the spring and ride along a rod or other track memberwhich serves to guide the path of the converters. They engage the tissuepenetrating member and/or delivery member (directly or indirectly) toproduce the desired motion. They are desirably configured to convertmotion of the spring along its longitudinal axis into orthogonal motionof the tissue penetrating member and/or delivery member thoughconversion in other directions is also contemplated. The motionconverters can have a wedge, trapezoidal or curved shape with othershapes also contemplated. In particular embodiments, the first motionconverter can have a trapezoidal shape and include a slot which engagesa pin on the tissue penetrating member that rides in the slot. The slotcan have a trapezoidal shape that mirrors or otherwise corresponds tothe overall shape of the converter and serves to push the tissuepenetrating member during the upslope portion of the trapezoid and thenpull it back during the down slope portion. In one variation, one orboth of the motion converters can comprise a cam or cam like devicewhich is turned by the spring and engages the tissue penetrating and/ordelivery member.

In other variations, the actuating mechanism can also comprise anelectro-mechanical device/mechanism such as a solenoid, or apiezoelectric device. In one embodiment, the piezoelectric device cancomprise a shaped piezoelectric element which has a non-deployed anddeployed state. This element can be configured to go into the deployedstate upon the application of a voltage and then return to thenon-deployed state upon the removal of the voltage. This and relatedembodiments allow for a reciprocating motion of the actuating mechanismso as to both advance the tissue penetrating member and then withdrawit.

The release element is coupled to at least one of the actuatingmechanism or a spring coupled to the actuating mechanism. In particularembodiments, the release element is coupled to a spring positionedwithin the capsule so as to retain the spring in a compressed state.Degradation of the release element releases the spring to actuate theactuation mechanism. In many embodiments, the release element comprisesa material configured to degrade upon exposure to chemical conditions inthe small or large intestine such as pH. Typically, the release elementis configured to degrade upon exposure to a selected pH in the smallintestine, e.g., 6.0, 6.3, 6.5, 6.7, 7.0, 7.1, 7.2, 7.3, 7.4, 8.0 orgreater. However, it can also be configured to degrade in response toother conditions in the small intestine, e.g., the presence of variousenzymes. In particular embodiments, the release element can beconfigured to degrade in response to particular chemical conditions inthe fluids in the small intestine such as those which occur afteringestion of a meal (e.g., a meal high in fats or proteins).

Biodegradation of the release element from one or more conditions in thesmall intestine (or other location in the GI tract) can be achieved byselection of the materials for the release element, the amount of crosslinking of those materials as well as the thickness and other dimensionsof the release elements. Lesser amounts of cross linking and or thinnerdimensions can increase the rate of degradation and vice versa. Suitablematerials for the release element can comprise biodegradable materialssuch as various enteric materials which are configured to degrade uponexposure to the higher pH or other condition in the small intestine. Theenteric materials can be copolymerized or otherwise mixed with one ormore polymers to obtain a number of particular material properties inaddition to biodegradation. Such properties can include withoutlimitation stiffness, strength, flexibility and hardness.

In particular embodiments, the release element can comprise a film orplug that fits over or otherwise blocks the guide tube and retains thetissue penetrating member inside the guide tube. In these and relatedembodiments, the tissue penetrating member is coupled to a spring loadedactuating mechanism such that when the release element is degradedsufficiently, it releases the tissue penetrating member which thensprings out of the guide tube to penetrate into the intestinal wall. Inother embodiments, the release element can be shaped to function as alatch which holds the tissue penetrating element in place. In these andrelated embodiments, the release element can be located on the exterioror the interior of the capsule. In the interior embodiments, the capsuleand guide tubes are configured to allow for the ingress of intestinalfluids into the capsule interior to allow for the degradation of therelease element.

In some embodiments, the actuating mechanism can be actuated by means ofa sensor, such as a pH or other chemical sensor which detects thepresence of the capsule in the small intestine and sends a signal to theactuating mechanism (or to an electronic controller coupled to theactuating mechanism to actuate the mechanism). Embodiments of a pHsensor can comprise an electrode-based sensor or it can be amechanically-based sensor such as a polymer which shrinks or expandsupon exposure to the pH or other chemical conditions in the smallintestine. In related embodiments, an expandable/contractible sensor canalso comprise the actuating mechanism itself by using the mechanicalmotion from the expansion or contraction of the sensor.

According to another embodiment for detecting that the swallowabledevice is in the small intestine (or other location in the GI tract),the sensor can comprise a strain gauge or other pressure/force sensorfor detecting the number of peristaltic contractions that the capsule isbeing subject to within a particular location in the intestinal tract.In these embodiments, the capsule is desirably sized to be gripped bythe small intestine during a peristaltic contraction). Differentlocations within the GI tract have different number of peristalticcontractions. The small intestine has between 12 to 9 contractions perminute with the frequency decreasing down the length of the intestine.Thus, according to one or more embodiments detection of the number ofperistaltic contractions can be used to not only determine if thecapsule is in the small intestine but the relative location within theintestine as well.

As an alternative or supplement to internally activated drug delivery,in another aspect of the invention, the user may externally activate theactuating mechanism to deliver drug by means of RF, magnetic or otherwireless signaling means known in the art. In these and relatedembodiments, the user can use a handheld device (e.g., a hand held RFdevice) which not only includes signaling means, but also means forinforming the user when the device is in the small intestine or otherlocation in the GI tract. The later embodiment can be implemented byincluding an RF transmitter on the swallowable device to signal to theuser when the device is in the small intestine or other location (e.g.,by signaling an input from the sensor). The same handheld device canalso be configured to alter the user when the actuating mechanism hasbeen activated and the selected drug(s) delivered. In this way, the useris provided confirmation that the drug has been delivered. This allowsthe user to take other appropriate drugs/therapeutic agents as well asmake other related decisions (e.g., for diabetics to eat a meal or notand what foods should be eaten). The handheld device can also beconfigured to send a signal to the swallowable device to over-ride theactuating mechanism and so prevent, delay or accelerate the delivery ofdrug. In use, such embodiments allow the user to intervene to prevent,delay or accelerate the delivery of drug based upon other symptomsand/or patient actions (e.g., eating a meal, deciding to go to sleep,exercise etc).

The user may also externally activate the actuating mechanism at aselected time period after swallowing the capsule. The time period canbe correlated to a typical transit time or range of transit times forfood moving through the user's GI tract to a particular location in thetract such as the small intestine.

Another aspect of the inventions provides therapeutic agent preparationsfor delivery into the wall of the small intestine (or other wall of alumen in the intestinal tract) using embodiments of the swallowabledevice described herein. The preparation comprises a therapeuticallyeffective dose of at least one therapeutic agent (e.g., insulin, ananti-seizure compound, NSAIDs, an antibiotic, etc). It may comprise asolid, liquid or combination of both and can include one or morepharmaceutical excipients. The preparation has a shape and materialconsistency to be contained in embodiments of the swallowable capsule,delivered from the capsule into the lumen wall and degrade within thelumen wall to release the dose of therapeutic agent. The preparation mayalso have a selectable surface area to volume ratio so as enhance orotherwise control the rate of degradation of the preparation in the wallof the small intestine or other body lumen. In various embodiments, thepreparation can be configured to be coupled to an actuator such as arelease element (and/or other components coupled to the release element)which has a first configuration in which the preparation is contained inthe capsule and a second configuration in which the preparation isadvanced out of the capsule and into the wall of the small intestine.The dose of the drug or other therapeutic agent in the preparation canbe titrated downward from that which would be required for conventionaloral delivery methods so that potential side effects from the drug canbe reduced.

Typically, though not necessarily, the preparation will be shaped andotherwise configured to be contained in the lumen of a tissuepenetrating member, such as a hollow needle which is configured to beadvanced out of the capsule and into the wall of the small intestine.Also, as described herein, in various embodiments, the preparationitself may comprise a tissue penetrating member shaped and configured tobe advanced into the wall of the small intestine or other lumen in theintestinal tract.

Another aspect of the invention provides methods for the delivery ofdrugs and the therapeutic agents into the walls of the GI tract usingembodiments of the swallowable drug delivery devices. Such methods canbe used for the delivery of therapeutically effective amounts of avariety of drugs and other therapeutic agents. These include a number oflarge molecule peptides and proteins which would otherwise requireinjection due to chemical breakdown in the stomach e.g., growth hormone,parathyroid hormone, insulin, interferons and other like compounds.Suitable drugs and other therapeutic agents which can be delivered byembodiments of invention include various chemotherapeutic agents (e.g.,interferon), antibiotics, antivirals, insulin and related compounds,glucagon like peptides (e.g., GLP-1, exenatide), parathyroid hormones,growth hormones (e.g., IFG and other growth factors), anti-seizureagents, immune suppression agents and anti parasitic agents such asvarious anti malarial agents. The dosage of the particular drug can betitrated for the patient's weight, age, condition or other parameter.

In various method embodiments, embodiments of the swallowable drugdelivery device can be used to deliver a plurality of drugs for thetreatment of multiple conditions or for the treatment of a particularcondition (e.g., a mixture of protease inhibitors for treatment HIVAIDS). In use, such embodiments allow a patient to forgo the necessityof having to take multiple medications for a particular condition orconditions. Also, they provide a means for facilitating that a regimenof two or more drugs is delivered and absorbed into the small intestineand thus, the blood stream at about the same time. Due to differences inchemical makeup, molecular weight, etc, drugs can be absorbed throughthe intestinal wall at different rates, resulting in differentpharmacokinetic distribution curves. Embodiments of the inventionaddress this issue by injecting the desired drug mixtures at about thesame time. This in turn, improves the pharmacokinetics and thus, theefficacy of the selected mixture of drugs.

In one embodiment, an ingestible device is suitable for swallowing intoa lumen of a gastrointestinal tract of a patient. The lumen has a wall.The device comprises a capsule sized to pass through the intestinaltract. A therapeutic agent preparation is disposable in the capsule. Thepreparation comprises at least one therapeutic agent and the therapeuticagent preparation would chemically degrade or impose a deleteriouseffect on the patient if released within the lumen of thegastrointestinal tract. An actuator is coupled to the therapeutic agentpreparation and has a first configuration and a second configuration.The preparation being retained within the capsule when the actuator isin the first configuration and the preparation is advanced from thecapsule and into the lumen wall by movement of the actuator from thefirst configuration to the second configuration such that thedeleterious effect or chemical degradation of the therapeutic agent inthe lumen is inhibited.

In another embodiment, a method for delivering a therapeutic agent intothe wall of a small intestine of a patient comprises swallowing a drugdelivery capsule device including a therapeutic agent, a release elementand a tissue penetrating member. The therapeutic agent would chemicallydegrade or impose a deleterious effect on the patient if released withina lumen of the gastrointestinal tract. The release element is releasedin the small intestine responsive to a condition in the small intestine;and the therapeutic agent is delivered into the wall of the smallintestine using the tissue penetrating member such that the deleteriouseffect or degradation of the therapeutic agent in the lumen isinhibited.

In yet another embodiment, a swallowable device for inserting atherapeutic agent preparation into the intestinal wall of a patient'sintestinal tract comprises a swallowable capsule sized to pass throughthe intestinal tract. The capsule has a capsule wall including anaperture. At least a portion of the capsule wall comprises a material orcoating which overlies the aperture and protects the capsule fromdegradation in the stomach and degrades in response to the pH in thesmall intestine. A tissue penetrating member includes a therapeuticagent preparation and a means for advancing the tissue penetratingmember from the capsule through the aperture and into the intestinalwall of the patient responsive to a selected pH in the intestine.

In another embodiment, a swallowable device for delivering a therapeuticagent preparation into the intestinal wall of a patient's intestinaltract comprises a swallowable capsule sized to pass through theintestinal tract. The capsule has a capsule wall including an aperture.An expandable member is disposed within capsule in at least a partiallynon expanded state. The expandable member includes a first portion and asecond portion separated by a separation valve which degrades uponexposure to a selected pH in the intestine. The first portion includes aliquid and the second portion includes a reactant configured to reactwith the liquid to produce a gas which expands the expandable memberwhen the valve degrades. The liquid from the first portion mixes withthe reactant in the second portion, to produce the gas which expands theexpandable member. A tissue penetrating member is formed at least inpart from a therapeutic agent preparation, the tissue penetratingmember, including a proximal and distal portion. The proximal portion isdetachably coupled to the expandable member. The tissue penetratingmember includes at least one retaining feature for retaining the tissuepenetrating member within the intestinal wall. Upon expansion of theexpandable member, the tissue penetrating member is advanced through theaperture into the intestinal wall where it is retained by the at leastone retaining feature so as to detach from the expandable member.

In still another embodiment, a swallowable device for delivering atherapeutic agent preparation into the intestinal wall of a patient'sintestinal tract comprises a swallowable capsule sized to pass throughthe intestinal tract. The capsule has a capsule wall including anaperture. An expandable member is disposed within capsule in at least apartially non expanded state. The expandable member includes a firstportion and second portion separated by a separation valve whichdegrades upon exposure to a selected pH in the intestine. The firstportion includes a liquid, the second portion includes a reactantconfigured to react with the liquid to produce a gas which expands theexpandable member when the valve degrades the liquid from the firstportion mixes with the reactant in the second portion, to produce thegas which expands the expandable member. A tissue penetrating member hasa lumen and a proximal and a distal portion. The proximal portion iscoupled to the expandable member such that upon expansion of theexpandable member, the tissue penetrating member is advanced through theaperture into the intestinal wall. At least one reservoir stores atherapeutic agent preparation. The reservoir is fluidicallly coupled totissue penetrating member lumen. The reservoir is configured andpositioned within the capsule to be collapsible by expansion of theexpandable member to eject the therapeutic agent from the reservoirthrough the lumen and into the intestinal wall.

In another embodiment, a swallowable device for delivering a drug intothe intestinal wall comprises a capsule sized to pass through theintestinal tract. A tissue penetrating member is positioned in thecapsule and contains the drug. The tissue penetrating member has atissue penetrating end for penetrating the intestinal wall. A deliverymember delivers the drug from the tissue penetrating member into tissue.An actuating mechanism is coupled to at least one of the tissuepenetrating member or the delivery member. The actuating mechanismconfigured to advance the tissue penetrating member into the intestinalwall and advance the delivery member to deliver the drug. A releaseelement is operatively coupled to the actuating mechanism, the releaseelement comprising a material configured to degrade upon exposure to aselected pH in the intestine such that upon degradation, the actuatingmechanism is actuated to release the tissue penetrating member andadvance the advanceable member to deliver drug into the intestinal wall.

In yet another embodiment, a method of drug delivery comprisesswallowing a drug delivery device comprising a capsule, a drug, anactuating mechanism, a release element and a tissue penetrating member.The release element is released in the small intestine responsive to acondition in the small intestine and the actuation mechanism is actuatedto deliver the drug into the wall of the small intestine using thetissue penetrating member.

Further details of these and other embodiments and aspects of theinvention are described more fully below, with reference to the attacheddrawing figures.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1a is a lateral viewing showing an embodiment of a swallowable drugdelivery device.

FIG. 1b is a lateral viewing showing an embodiment of a system includinga swallowable drug delivery device.

FIG. 1c is a lateral viewing showing an embodiment of a kit including aswallowable drug delivery device and a set of instructions for use.

FIG. 1d is a lateral viewing showing an embodiment of a swallowable drugdelivery device including a drug reservoir.

FIG. 2 is a lateral view illustrating an embodiment of the swallowabledrug delivery device having a spring loaded actuation mechanism foradvancing tissue penetrating members into tissue.

FIG. 3 is a lateral view illustrating an embodiment of the swallowabledrug delivery device having a spring loaded actuation mechanism having afirst motion converter.

FIG. 4 is a lateral view illustrating an embodiment of the swallowabledrug delivery device having a spring loaded actuation mechanism havingfirst and a second motion converter.

FIG. 5 is a perspective view illustrating engagement of the first andsecond motion converters with the tissue penetrating member and deliverymembers.

FIG. 6 is a cross sectional view illustrating an embodiment of theswallowable drug delivery device having a single tissue penetratingmember and an actuating mechanism for advancing the tissue penetratingmember.

FIG. 7a is a cross sectional view illustrating an embodiment of theswallowable drug delivery device having a multiple tissue penetratingmembers and an actuating mechanism for advancing the tissue penetratingmembers.

FIG. 7b is a cross sectional view illustrating deployment of the tissuepenetrating members of the embodiment of FIG. 7a to deliver medicationto a delivery site and anchor the device in the intestinal wall duringdelivery.

FIGS. 8a-8c are side view illustrating positioning of the drug deliverydevice in the small intestine and deployment of the tissue penetratingmembers to deliver drug; FIG. 8a shows the device in the small intestineprior to deployment of the tissue penetrating members with the releaseelement in tact; FIG. 8b shows the device in the small intestine withthe release element degraded and the tissue penetrating elementsdeployed; and FIG. 8c shows the device in the small intestine with thetissue penetrating elements retracted and the drug delivered.

FIG. 9a shows an embodiment of a swallowable drug delivery deviceincluding a capsule having bio-degradable seams positioned to producecontrolled degradation of the capsule in the GI tract.

FIG. 9b shows the embodiment of FIG. 9a after having been degraded inthe GI tract into smaller pieces.

FIG. 10 shows an embodiment of a capsule having biodegradable seamsincluding pores and/or perforations to accelerate biodegradation of thecapsule.

FIG. 11 is a lateral viewing illustrating use of an embodiment of aswallowable drug delivery device including transit of device in the GItract and operation of the device to deliver drug.

FIG. 12 is a lateral cross sectional view illustrating an embodiment ofthe swallowable drug device having an expandable member such as anexpandable balloon.

FIG. 13 is a lateral view illustrating an embodiment of an expandableballoon in an inflated state inside an embodiment of the swallowablecapsule

FIG. 14a-14c are lateral views illustrating inflation of the expandableballoon using chemical reactants, FIG. 14a shows the balloon in anon-inflated state with the separation valve closed; FIG. 14b shows theballoon with valve open and mixing of the chemical reactants; and FIG.14c shows the balloon in an inflated state.

FIG. 15 shows an embodiment of a separation valve having pinchingfeatures.

FIG. 16a-16c are lateral views illustrating use of a swallowable drugdelivery device having a biodegradable coated capsule coating and abiodegradable separation valve to initiate inflation of the balloon inthe small intestine. FIG. 16a shows the balloon in a non-inflated statewith the capsule coating intact and the separation valve closed; FIG.16b shows the capsule coating degraded and resulting ingress ofintestinal fluid into the capsule interior to make contact with theisolation valve; and FIG. 16c shows the degradation and opening of theisolation valve from contact with intestinal fluid.

FIG. 17a shows is cross sectional view of an embodiment of a separationvalve having a beam like structure.

FIG. 17b shows is a top view of the embodiment of FIG. 17 a.

FIG. 18 shows an embodiment of a separation valve comprising a collarvalve

FIGS. 19a and 19b show an embodiment of the expandable balloon having adeflation valve comprising a biodegradable section of the balloon wall.

FIG. 20a is a side view of an embodiment of the tissue penetratingmember.

FIG. 20b is a bottom view of an embodiment of the tissue penetratingmember illustrating placement of the tissue retaining features.

FIG. 20c is a side view of an embodiment of the tissue penetratingmember having a separate drug containing section.

FIG. 21a is a lateral view showing use of an advancement member tocouple the tissue penetrating member to the expandable balloon.

FIG. 21b is a bottom view showing an embodiment of an advancement memberhaving a larger surface area than the tissue penetrating member so as tofunction as a force concentrating element.

FIG. 22a is a lateral view showing use of an advancement member and anunderlying platform to couple one or more tissue penetrating members tothe expandable balloon.

FIG. 22b is a lateral view showing an embodiment of a platform havingmultiple advancement members and tissue penetrating members.

FIGS. 23a and 23b are lateral views illustrating use of an embodiment ofa swallowable device having platforms and tissue penetrating membersplaced on opposite sides of the balloon to achieve bilateral deploymentof the tissue penetrating members; FIG. 23a shows the balloon in a noninflated state and FIG. 23b shows the balloon inflated with thepenetrating members deployed.

FIGS. 24a and 24b are cross sectional views illustrating use of anembodiment of a swallowable device having tissue penetrating membersdistributed around the entire perimeter of the balloon; FIG. 24a showsthe balloon in a non inflated state and FIG. 24b shows the ballooninflated and the penetrating members placed in a distributed patternwithin the intestinal wall.

FIGS. 25a and 25b are lateral views illustrating use of an embodiment ofa swallowable device having drug reservoirs compressible by expansion ofthe inflatable balloon; FIG. 25a shows the balloon in a non inflatedstate, and FIG. 25b shows the balloon inflated with drug injected fromthe reservoir into the intestinal wall.

FIG. 26 is a lateral view illustrating an embodiment of a manifold forcoupling two or more drug reservoirs to a hollow tissue penetratingmember.

FIGS. 27a and 27b shows an embodiment of a colar type separation valveincorporating use of an expandable pH sensor for opening of the valve;FIG. 27a shows the valve in the closed position and FIG. 27b shows thevalve in the open position.

FIGS. 28a-28b are cross sectional views of an embodiment of a beam likeseparation valve incorporating use of a contractible pH sensor foropening of the valve; FIG. 28a shows the valve in the closed positionand FIG. 28b shows the valve in the open position.

FIGS. 29a-29b , show an embodiment of a capsule having tearable seamsarranged in a radial or lateral pattern for tearing of the capsule byinflation of the expandable balloon; FIG. 29a shows the capsule prior toinflation and FIG. 29b shows the capsule broken into pieces by theinflation of the balloon.

FIG. 30 shows an embodiment of a balloon tearable capsule fabricatedfrom separate portions joined by seams, which can be torn by inflationof the expandable balloon.

DETAILED DESCRIPTION OF THE INVENTION

Embodiments of the invention provide devices, systems and methods fordelivering medications in to various locations in the body. As usedherein, the term “medication” refers to a medicinal preparation in anyform which can include drugs or other therapeutic agents as well as oneor more pharmaceutical excipients. Many embodiments provide aswallowable device for delivering medication within the GI tract.Particular embodiments provide a swallowable device such as a capsulefor delivering medications to the wall of the small intestine or otherGI organ.

Referring now to FIGS. 1-11, embodiments of a device 10 for the deliveryof medication 100 to a delivery site DS in the intestinal tract,comprises a capsule 20 including at least one aperture 26, an expandablemember 30, guide tube 30, and one or more tissue penetrating members 40containing a medication 100. The tissue penetrating member 40 can beformed at least in part from medication 100, and/or contain a section orcompartment 42 formed from or containing medication 100 that is integralwith the tissue penetrating member 40 positioned or otherwiseadvanceable in the at least one guide tube, a delivery member 50, anactuating mechanism 60 and release element 70. Medication 100 alsodescribed herein as preparation 100, typically comprises at least onedrug or therapeutic agent 101 and may include one or more pharmaceuticalexcipients known in the art.

Device 10 including tissue penetrating member 40 can be configured forthe delivery of liquid, semi-liquid or solid forms of medication 100 orall three. Solid forms of medication/preparation 100 can include bothpowder or pellet. Semi liquid can include a slurry or paste. Whateverthe form, medication/preparation 100 desirably has a shape and materialconsistency allowing the medication to be advanced out of the device,into the intestinal wall (or other luminal wall in the GI tract) andthen degrade in the intestinal wall to release the drug or othertherapeutic agent 101. The material consistency can include one or moreof the hardness, porosity and solubility of the preparation (in bodyfluids). The material consistency can be achieved by one or more of thefollowing: i) the compaction force used to make the preparation; ii) theuse of one or more pharmaceutical disintegrants known in the art; iii)use of other pharmaceutical excipients; iv) the particle size anddistribution of the preparation (e.g., micronized particles); and v) useof micronizing and other particle formation methods known in the art.Suitable shapes for preparation 100 can include cylindrical, cubical,rectangular, conical, spherical, hemispherical and combinations thereof.Also, the shape can be selected so as to define a particular surfacearea and volume of preparation 100 and thus, the ratio between the two.The ratio of surface area to volume can in turn, be used to achieve aselected rate of degradation within the intestinal or other lumen wall.Larger ratios (e.g., larger amounts of surface area per unit volume) canbe used to achieve faster rates of degradation and vice versa. Inparticular embodiments, the surface area to volume ratio can be in therange of about 1:1 to 100:1, with specific embodiments of 2:1, 5:1,20:1, 25:1, 50:1 and 75:1. Medication/preparation 100 will typically bepre-packed within a lumen 44 of tissue penetrating members 40, but canalso be contained at another location within an interior 24 of capsule20, or in the case of a liquid or semi-liquid, within an enclosedreservoir 27. The medication can be pre-shaped to fit into the lumen orpacked for example, in a powder form. Typically, the device 10 will beconfigured to deliver a single drug 101 as part of medication 100.However in some embodiments, the device 10 can be configured fordelivery of multiple drugs 101 including a first second, or a third drugwhich can be compounded into a single or multiple medications 100. Forembodiments having multiple medications/drugs, the medications can becontained in separate tissue penetrating members 40 or within separatecompartments or reservoirs 27 within capsule 20. In another embodiment,a first dose 102 of medication 100 containing a first drug 101 can bepacked into the penetrating member(s) 40 and a second dose 103 ofmedication 100 (containing the same or a different drug 101) can becoated onto the surface 25 of capsule as is shown in the embodiment ofFIG. 1a . The drugs 101 in the two doses of medication 102 and 103 canbe the same or different. In this way, a bimodal pharmacokinetic releaseof the same or different drugs can be achieved. The second dose 103 ofmedication 100 can have an enteric coating 104 to ensure that it isreleased in the small intestine and achieve a time release of themedication 100 as well. Enteric coating 104 can include one or moreenteric coatings described herein or known in the art.

A system 11 for delivery of medication 100 into the wall of the smallintestine or other location within the GI tract, may comprise device 10,containing one or more medications 100 for the treatment of a selectedcondition or conditions. In some embodiments, the system may include ahand held device 13, described herein for communicating with device 10as is shown in the embodiment of FIG. 1b . System 11 may also beconfigured as a kit 14 including system 11 and a set of instructions foruse 15 which are packaged in packaging 12 as is shown in the embodimentof FIG. 1c . The instructions can indicate to the patient when to takethe device 10 relative to one or more events such as the ingestion of ameal or a physiological measurement such as blood glucose, cholesterol,etc. In such embodiments, kit 14 can include multiple devices 10containing a regimen of medications 100 for a selected period ofadministration, e.g., a day, week, or multiple weeks depending upon thecondition to be treated.

Capsule 20 is sized to be swallowed and pass through the intestinaltract. The size can also be adjusted depending upon the amount of drugto be delivered as well as the patient's weight and adult vs. pediatricapplications. Typically the capsule will have a tubular shape withcurved ends similar to a vitamin. In these and related embodiment,capsule lengths 20L can be in the range of 0.5 to 2 inches and diameters20D in the range of 0.1 to 0.5 inches with other dimensionscontemplated. The capsule 20 includes a capsule wall 21 w, having anexterior surface 25 and an interior surface 24 defining an interiorspace or volume 24 v. The capsule wall 21 w includes volume 24 and anouter surface 25 having one or more apertures 26 sized for the outwardadvancement of tissue penetrating members 40. via guide tubes 30. Inaddition to the other components of device 10, (e.g., the expandablemember, actuation mechanism etc.) the interior volume can include one ormore compartments or reservoirs 27.

One or more portions of capsule 20 can be fabricated from variousbiocompatible polymers known in the art, including various biodegradablepolymers which in a preferred embodiment can comprise PGLA(polylactic-co-glycolic acid). Other suitable biodegradable materialsinclude various enteric materials described herein as well as lactide,glycolide, lactic acid, glycolic acid, para-dioxanone, caprolactone,trimethylene carbonate, caprolactone, blends and copolymers thereof.

Use of biodegradable materials for capsule 20, including biodegradableenteric materials allows the capsule to degrade in whole or part tofacilitate passage through the GI system after drug deliver. As isdescribed in further detail herein, in various embodiments, capsule 20can include seams 22 of bio-degradable material so as to controllablydegrade into smaller pieces 23 which are more easily passed through theintestinal tract.

Additionally, in various embodiments, the capsule 20 can include variousradio-opaque or echogenic materials for location of the device usingfluoroscopy, ultrasound or other medical imaging modality. In specificembodiments, all or a portion of the capsule can includeradio-opaque/echogenic markers 20 m as is shown in the embodiment ofFIGS. 1a and 1b . In use, such materials not only allow for the locationof device 10 in the GI tract, but also allow for the determination oftransit times of the device through the GI tract.

Expandable member 30 can comprise a variety of expandable devices shapedand sized to fit within capsule 20, but will typically comprise anexpandable balloon 30. Other suitable expandable members include variousshape memory devices, and/or chemically expandable polymer deviceshaving an expanded shape and size corresponding to the interior volume24 v of the capsule 20. For ease of discussion, expandable member 30will now be referred to as balloon 30, but other embodiments are equallyapplicable. Balloon 30 will typically be attached to an interior surface24 of the capsule 20 in at least a partially non-expanded state. Meansof attachment can include the use of various adhesive known in themedical device arts. The balloon can be packed inside capsule 20 in afurled or other compact configuration to conserve space within theinterior portion of the capsule. Furling may be achieved by placement ofseparation valve 50 over a selected portion of the un-inflated balloon30. In a particular embodiments, furling can be facilitated by the useof a collar type separation valve 55 described herein that is placedaround the un-inflated balloon to hold in a furled configuration. Inanother approach, furling can also be achieved by the use of one or morepre-formed creases 30 c placed along the balloon in a lateral, spiral orother configuration. In preferred embodiments, tissue penetratingmembers 40 are positioned within guide tubes 30 which serve to guide andsupport the advancement of members 40 into tissue such as the wall ofthe small intestine or other portion of the GI tract. In otherembodiments, tissue penetrating members 40 can be positioned in capsule20 without guide tubes. The tissue penetrating members 40 will typicallycomprise a hollow needle or other like structure and will have a lumen44 and a tissue penetrating end 45 for penetrating a selectable depthinto the intestinal wall IW. Member 40 may also include a pin 41 forengagement with a motion converter 90 described herein. The depth ofpenetration can be controlled by the length of member 40, theconfiguration of motion converter 90 described herein as well as theplacement of a stop or flange 40 s on member 40 which can, in anembodiment, correspond to pin 41 described herein. Medication 100 willtypically be delivered into tissue through lumen 44. In manyembodiments, lumen 44 is pre-packed with the desired medication 100which is advanced out of the lumen using delivery member 50 or otheradvancement means (e.g. by means of force applied to a collapsibleembodiment of member 40). As an alternative, medication 100 can beadvanced into lumen 44 from another location/compartment in capsule 20.In some embodiments, all or a portion of the tissue penetrating member40 can be fabricated from medication 100 itself. In these and relatedembodiments, the medication can have a needle or dart-like structure(with or without barbs) configured to penetrate and be retained in theintestinal wall such as the wall of the small intestine. The dart can besized and shaped depending upon the medication, dose and desired depthof penetration into the intestinal wall. Medication 100 can be formedinto darts, pellets or other shapes using various compression moldingand other related methods known in the pharmaceutical arts.

Balloon 30 can comprise various polymers known in the medical devicearts, but preferably comprises non-compliant polymers such as PET(Polyethylene Teraphalate) and other non compliant materials known inthe art. It can be fabricated using various balloon blowing methodsknown in the balloon catheters arts (e.g., mold blowing) to have a shape30 s and size which corresponds approximately to the interior volume 24v of capsule 20. Suitable shapes 30 s for balloon 30 include variouscylindrical shapes having tapered or curved end portions 31 (an exampleof such a shape including a hot dog). In some embodiments, the inflatedsize of balloon 30, including its diameter 30D can be slightly largerthan capsule 20 so as to cause the capsule to come apart from the forceof inflation, (e.g., due to hoop stress). Desirably, the walls 32 ofballoon 30 will be thin and can have a wall thickness 33 in the range of0.005 to 0.0001″ more preferably, in the range of 0.001 to 0.0001, withspecific embodiments of 0.002, 0.001, and 0.0005). In variousembodiments, device 10 can include a second 42 and a third 43 tissuepenetrating member 40 as is shown in the embodiments of FIGS. 7a and 7b, with additional numbers contemplated. Each tissue penetrating member40 can be used to deliver the same or a different medication 100 as wellas different doses of the same drug. In preferred embodiments, thetissue penetrating members 40 can be substantially symmetricallydistributed around the perimeter 21 of capsule 20 so as to anchor thecapsule onto the intestinal wall IW during delivery of medications 100.Anchoring capsule 20 in such a way reduces the likelihood that thecapsule will be displaced or moved by peristaltic contractions occurringduring delivery of the medication. In specific embodiments, the amountof anchoring force can be adjusted to the typical forces applied duringperistaltic contraction of the small intestine. Anchoring can be furtherfacilitated by configured some or all of tissue penetrating members 40to have a curved or arcuate shape.

Balloon 230 also will typically include at least a first and a secondportion or compartment 234 and 235 which are separated by a separationvalve, delivery member, or other separation means which separates thecontents of each compartment. In many embodiments, compartments 234 and235 will have at least a small connecting section 236 between them whichis where separation valve 250 will typically be placed. A liquid 239,typically water, can be disposed within first compartment 234 and one ormore reactants 260 disposed in second compartment 235 (which typicallyare solid though liquid may also be used) as is shown in the embodimentof FIG. 14a . When valve 250 opens (e.g., from degradation caused byfluids within the small intestine) liquid 239 enters compartment 235 (orvice versa or both), the reactant(s) 260 mix with the liquid and producea gas 263 such as carbon dioxide which expands balloon 230 as is shownin the embodiments of FIGS. 14b-14c . Expansion of balloon 230 isconfigured to advance medication 100 through the tissue penetratingmember 240 into the intestinal wall IW as will be explained more fullyherein. Accordingly, at least a portion of the delivery member 250 isadvanceable within the tissue penetrating member lumen 244 and thusmember 250 has a size and shape (e.g., a piston like shape) configuredto fit within the delivery member lumen 244 or other chamber orcompartment within tissue penetrating member 240.

Reactants 260 will typically include at least a first and a secondreactant, 261 and 262 for example, an acid such as citric acid and abase such as sodium hydroxide. Additional numbers of reactants are alsocontemplated. For embodiments using citric acid and sodium hydroxide,the ratio's between the two reactants (citric acid to sodium hydroxide)can be in the range of 1:1 to 1:4, with a specific ratio of 1:2.Desirably, solid reactants 260 have little or no absorbed water.Accordingly, one or more of the reactants, such as sodium hydroxide canbe pre-dried (e.g., by vacuum drying) before being placed within balloon230. Other reactants 260 including other acids, e.g., ascetic acid andbases are also contemplated. The amounts of particular reactants 260,including combinations of reactants can be selected to produceparticular pressures using known stoichiometric equations for theparticular chemical reactions as well as the inflated volume of theballoon and the ideal gas law (e.g., PV=nRT)

In some embodiments, the distal end 50 d of the delivery member (the endwhich is advanced into tissue) can have a plunger element 51 whichadvances the medication within the tissue penetrating member lumen 44and also forms a seal with the lumen. Plunger element 51 can be integralor attached to delivery member 50. Preferably, delivery member 50 isconfigured to travel a fixed distance within the needle lumen 44 so asto deliver a fixed or metered dose of drug into the intestinal wall IW.This can be achieved by one or more of the selection of the diameter ofthe delivery member (e.g., the diameter can be distally tapered), thediameter of the tissue penetrating member (which can be narrowed at itsdistal end), use of a stop, and/or the actuating mechanism. However insome embodiments, the stroke or travel distance of member 50 can beadjusted in situ responsive to various factors such as one or moresensed conditions in the GI tract. In situ adjustment can be achievedthrough use of logic resource 29 (including controller 29 c) coupled toan electro-mechanical embodiment of actuating mechanism 60. This allowsfor a variable dose of medication and/or variation of the distance themedication is injected into the intestinal wall.

Various embodiments of the invention provide a number of structures andconfigurations for a separation valve 250 or other separation means 250.As is described below, in one or more embodiments, valve 250 maycomprise a beam like structure, or collar type valve. Still otherstructures are considered. In one or more of these embodiments, valve250 can include one or more pinching features 251 such as a ridge whichengages a depression or other mating feature 252 on the internal surface224 of capsule 220 as is shown in the embodiment of FIG. 15. In use,pinching features 251 provide for the application of additional force onthe balloon wall 232 beneath the pinching feature and redundancy to theseal. Valve 250 may include multiple pinching features 251 to create aseal under each feature.

Actuating mechanism 60 can be coupled to at least one of the tissuepenetrating member 40 or delivery member 50. The actuating mechanism isconfigured to advance tissue penetrating member 40 a selectable distanceinto the intestinal wall IW as well as advance the delivery member todeliver medication 100 and then withdraw the tissue penetrating memberfrom the intestinal wall. In various embodiments, actuating mechanism 60can comprise a spring loaded mechanism which is configured to bereleased by release element 70. Suitable springs 80 can include bothcoil (including conical shaped springs) and leaf springs with otherspring structures also contemplated. In particular embodiments, spring80 can be substantially cone-shaped to reduce the length of the springin the compressed state even to the point where the compressed length ofthe spring is about the thickness of several coils (e.g., two or three)or only one coil.

Also in various embodiments, separation valve 250 can be configured toopen in a number of ways and responsive to a number of conditions withinthe GI tract. In many embodiments, the separation valve 250 will beconfigured to open by having one or more portions degrade in response tothe higher pH or other conditions found within the small intestine suchthat upon degradation, the valve opens. As an alternative or additionalapproach, separation valve 250 may also be configured to open inresponse to compressive forces applied by a peristaltic contractionwithin the small intestine. In still another approach, separation valve250 may be a time-release valve configured to open after a certainperiod of time after a trigger event, e.g., an activation step initiatedby the patient such as the pealing of a tab or pressing of a button.

In particular embodiments actuating mechanism 60 can comprise a spring80, a first motion converter 90, and a second motion converter 94 and atrack member 98 as is shown in the embodiments of FIGS. 2, 4 and 8 a-8c. The release element 70 is coupled to spring 80 to retain the springin a compressed state such that degradation of the release elementreleases the spring. Spring 80 may be coupled to release element 70 by alatch or other connecting element 81. First motion converter 90 isconfigured to convert motion of spring 80 to advance and withdraw thetissue penetrating member 40 in and out of the intestinal wall or othertissue. The second motion converter 94 is configured to convert motionof the spring 80 to advance the delivery member 50 into the tissuepenetrating member lumen 44. Motion converters 90 and 94 are pushed bythe spring and ride along a rod or other track member 98 which fits intoa track member lumen 99 of converter 90. The track member 98 whichserves to guide the path of the converters 90. Converters 90 and 94engage the tissue penetrating member 40 and/or delivery member 50(directly or indirectly) to produce the desired motion. They have ashape and other characteristics configured to convert motion of thespring 80 along its longitudinal axis into orthogonal motion of thetissue penetrating member 40 and/or delivery member 50 though conversionin other directions is also contemplated. The motion converters can havea wedge, trapezoidal or curved shape with other shapes alsocontemplated. In particular embodiments, the first motion converter 90can have a trapezoidal shape 90 t and include a slot 93 which engages apin 41 on the tissue penetrating member that rides in the slot as isshown in the embodiments of FIGS. 2, 3 and 4. Slot 93 can also have atrapezoidal shape 93 t that mirrors or otherwise corresponds to theoverall shape of converter 90. Slot 93 serves to push the tissuepenetrating member 40 during the upslope portion 91 of the trapezoid andthen pull it back during the down slope portion 92. In one variation,one or both of the motion converters 90 and 94 can comprise a cam or camlike device (not shown). The cam can be turned by spring 80 so as toengage the tissue penetrating and/or delivery members 40 and 50. One ormore components of mechanism 60 (as well as other components of device10) including motion converters 90 and 94 can be fabricated usingvarious MEMS-based methods known in the art so as to allow for selectedamounts of miniaturization to fit within capsule 10. Also as isdescribed herein, they can be formed from various biodegradablematerials known in the art.

Embodiments of a degradable separation valve 250 can be positioned in avariety of locations on or within capsule 220 so as to exposed to anddegraded by the intestinal fluids. While at least a portion of the valvemay be exposed to the capsule exterior surface 225, typically, the valvewill be positioned within the capsule interior 224 v where it is exposedto intestinal fluids which enter through the at least one aperture 226or other opening. In these and related embodiments, at least a portionof the capsule exterior surface 225 including the portion containing theat least one aperture 226 is desirably coated with a protective layer orcoating 220 c, such as an enteric coating which also degrades inresponse to pH or other conditions within the small intestine.Typically, the entire capsule will be so coated, however in someembodiments only a portion over apertures 226 will be coated. Suchcoatings provide a protective seal 226 s over the at least one aperture226 so that digestive fluids do not enter the capsule interior 224 v andstart to degrade the separation valve 250 until the capsule has reachedthe small intestine. The embodiments of FIGS. 16a-16c illustrate thesequence of degradation of the coating, ingress of intestinal or otherfluid F into the capsule interior and subsequent degradation of theseparation valve. In use, embodiments of device 210 employing adegradable coating 220 c over the aperture 226 and a degradable valve250 provide a primary and secondary seal for assuring that balloon 230does not prematurely expand and deploy its tissue penetrating members240 until capsule 220 has reached the small intestine.

In other variations, the actuating mechanism 60 can also comprise anelectro-mechanical device/mechanism such as a solenoid, or apiezoelectric device. In one embodiment, a piezoelectric device used inmechanism 60 can comprise a shaped piezoelectric element which has anon-deployed and deployed state. This element can be configured to gointo the deployed state upon the application of a voltage and thenreturn to the non-deployed state upon the removal of the voltage. Thisand related embodiments allow for a reciprocating motion of theactuating mechanism 60 so as to both advance the tissue penetratingmember and then withdraw it. The voltage for the piezoelectric elementcan be obtained generated using a battery or a piezoelectric basedenergy converter which generates voltage by mechanical deformation suchas that which occurs from compression of the capsule 20 by a peristalticcontraction of the small intestine around the capsule. Furtherdescription of piezoelectric based energy converters is found in U.S.patent application Ser. No. 12/556,524 which is fully incorporated byreference herein for all purposes. In one embodiment, deployment oftissue penetrating members 40 can in fact be triggered from aperistaltic contraction of the small intestine which provides themechanical energy for generating voltage for the piezoelectric element.

According to one or more embodiments, separation valve 250 may comprisea beam-like structure 258 that is placed within capsule 220 to compressand seal the portion of the balloon 236 between the first and secondcompartments 234 and 235 as is shown in the embodiment of FIGS. 17a and17b . Beam 258 is desirably constructed of one more degradable materialsdescribed herein, e.g., PGLA, cellulose, etc. which degrade in responseto the fluids found within the small intestine. When beam 258 degrades,the compressive forces of the balloon are released and contents from thefirst and second compartments 234 and 235 mix causing balloon expansionas described herein. Beam 258 can be attached at one or both sides ofthe interior surface 224 of the capsule. Typically, the beam will beplaced proximate a central portion 236 of balloon 230, though otherlocations are also contemplated. In preferred embodiments, the beam 258is positioned in radially oriented fashion with respect to balloonlateral axis 201 a, attached to the radial sides 220 rs of capsuleinterior surface 224 as is shown in the embodiment of FIGS. 17a and 17b. However, beam 258 may also be attached to the lateral ends 201 e ofthe capsule interior surface. Preferably, in either of these twoembodiments, beam 258 is attached to capsule interior surface 224 usingan interference fit so that the beam can be snapped into place withinthe capsule using pick and place and other like methods known in themanufacturing arts. In specific embodiments, interior surface 224 caninclude notches 224 n for placement of beam ends 258 e to allow a snapor press fit of the beam 258 into the capsule 220.

Release element 70 will typically be coupled to the actuating mechanism60 and/or a spring coupled to the actuating mechanism; however otherconfigurations are also contemplated. In preferred embodiments, releaseelement 70 is coupled to a spring 80 positioned within capsule 20 so asto retain the spring in a compressed state 85 as shown in the embodimentof FIG. 2. Degradation of the release element 70 releases spring 80 toactuate actuation mechanism 60. Accordingly, release element 70 can thusfunction as an actuator 70 a (actuator 70 a may also include (singularlyor coupled to release element 70) spring 80 and other elements ofmechanism 60). As is explained further below, actuator 70 a has a firstconfiguration where the therapeutic agent preparation 100 is containedwithin capsule 20 and a second configuration where the therapeutic agentpreparation is advanced from the capsule into the wall of the smallintestine or other luminal wall in the intestinal tract.

In many embodiments, release element 70 comprises a material configuredto degrade upon exposure to chemical conditions in the small or largeintestine such as pH. Typically, release element 70 is configured todegrade upon exposure to a selected pH in the small intestine, e.g.,7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6 8.0 or greater. The release elementcan also be configured to degrade within a particular range of pH suchas, e.g., 7.0 to 7.5. In particular embodiments, the pH at which releaseelement 70 degrades (defined herein as the degradation pH) can beselected for the particular drug to be delivered so as to release thedrug at a location in small intestine which corresponds to the selectedpH. Further, for embodiments of device 10 having multiple medications100, the device can include a first release element 70 (coupled to anactuating mechanism for delivering a first drug) configured to degradeat first pH and a second release element 70 (coupled to an actuatingmechanism for delivering a second drug) configured to degrade at asecond pH (with additional numbers of release elements contemplated forvarying number of drugs).

According to another embodiment shown in FIG. 18, the separation valve250 can comprise a collar valve 255 including a connecting 236 of theexpandable member 230 with an overlying constricting collar 255 c madefrom biodegradable material. Collar 255 c holds connection section 236closed and releases it when the collar is degraded.

Release element 70 can also be configured to degrade in response toother conditions in the small intestine (or other GI location). Inparticular embodiments, the release element 70 can be configured todegrade in response to particular chemical conditions in the fluids inthe small intestine such as those which occur after ingestion of a meal(e.g., a meal containing fats, starches or proteins). In this way, therelease of medication 100 can be substantially synchronized or otherwisetimed with the digestion of a meal. Such embodiments are particularlyuseful for the delivery of medication to control levels of bloodsugar/glucose (e.g., insulin), serum cholesterol and serumtriglycerides.

In addition to release valve 250, the balloon or other expandable member230 will also typically include a deflation valve 270 which serves todeflate balloon 230 after inflation. Deflation valve 270 can comprisebiodegradable materials which are configured to degrade upon exposure tothe fluids in the small intestine and/or liquid in one of thecompartments of the balloon so as to create an opening or channel forescape of gas within balloon. In one embodiment shown in FIG. 19a , thedeflation valve 270 can comprise a biodegradable section 271 positionedon an end portion 231 of the balloon 230 so as to join opposing ends ofthe balloon wall 232 together. In this and related embodiments, whendegradable section 271 degrades from exposure to the liquid, balloonwall 232 tears or otherwise comes apart providing for a high assuranceof rapid deflation. Multiple degradable sections 271 can be placed atvarious locations within balloon wall 232 is shown in the embodiment ofFIG. 19b , to provide an even higher degree of reliability in deflation.Desirably, sections 271 are only placed within the wall 232 ofcompartment 235. For embodiments where the deflation valve 270 isdegraded by fluids within the small intestine, degradation of the valvecan be facilitated by configuring inflated balloon 230 to break apartcapsule 220 into two or more pieces so that large sections of theballoon are directly exposed to degrading fluids within the smallintestine. This can be achieved by fabricating capsule 220 from separateparts (e.g., two halves mechanically fit together) and/or through theuse of seams 222 in the capsule wall as is described herein.

Various approaches are contemplated for biodegradation of releaseelement 70. In particular embodiments, biodegradation of release element70 from one or more conditions in the small intestine (or other locationin the GI tract) can be achieved by one or more of the following: i)selection of the materials for the release element, ii) the amount ofcross linking of those materials; and iii) the thickness and otherdimensions of the release element. Lesser amounts of cross linking andor thinner dimensions can increase the rate of degradation and visaversa. Suitable materials for the release element can comprisebiodegradable materials such as various enteric materials which areconfigured to degrade upon exposure to the higher pH in the intestines.Suitable enteric materials include, but are not limited to, thefollowing: cellulose acetate phthalate, cellulose acetate trimellitate,hydroxypropyl methylcellulose phthalate, polyvinyl acetate phthalate,carboxymethylethylcellulose, co-polymerized methacrylic acid/methacrylicacid methyl esters as well as other enteric materials known in the art.The selected enteric materials can be copolymerized or otherwisecombined with one or more other polymers to obtain a number of otherparticular material properties in addition to biodegradation. Suchproperties can include without limitation stiffness, strength,flexibility and hardness.

Additionally, as further backup for insured deflation, one or morepuncture elements 72 can be attached to the inside surface 24 of thecapsule wall such that when the balloon fully deflates it is contactsand is punctured by the puncture element. Puncture elements 72 cancomprise short protrusions from surface 24 having a pointed tip 73. Inanother alternative or additional embodiment of means for balloondeflation, one or more of the tissue penetrating members 40 can bedirectly coupled to balloon wall 32 and configured to tear away from theballoon when they detach, tearing the balloon wall in the process.

In alternative embodiments, the release element 70 can comprise a filmor plug 70 p that fits over or otherwise blocks guide tubes 30 andretains the tissue penetrating member 40 inside the guide tube (FIG. 1c). In these and related embodiments, tissue penetrating member 40 iscoupled to a spring loaded actuating mechanism such that when therelease element is degraded sufficiently, it releases the tissuepenetrating member which then springs out of the guide tube to penetrateinto the intestinal wall. In still other embodiments, release element 70can be shaped to function as a latch which holds the tissue penetratingmember 40 in place. In these and related embodiments, the releaseelement can be located on the exterior or the interior of capsule 20. Inthe latter case, capsule 20 and/or guide tubes 30 can be configured toallow for the ingress of intestinal fluids into the capsule interior toallow for the degradation of the release element.

Tissue penetrating member 40 can be fabricated from various drugs andother therapeutic agents 101 as well as one or more biodegradablepolymers to provide desired structural properties to the penetratingmember (e.g., column strength) and/or control the release of drug.Referring now to FIGS. 20a-20c , in many embodiments, the penetratingmember 40 can be formed to have a shaft 44 and a needle tip 45 or otherpointed tip 45 so as to readily penetrate tissue of the intestinal wallas shown in the embodiment of FIG. 20a . Tip 45 may comprise degradablematerials (within the body of the tip or as a coating), such as sucrosewhich increase the hardness and tissue penetrating properties of thetip. Once placed in the intestinal wall, the penetrating member 40 isdegraded by the interstitial fluids within the wall tissue, the drugdissolves in those fluids and is absorbed into the blood stream.Penetrating member 40 will also typically include one or more tissueretaining features 43 such as a barb or hook to retain the penetratingmember within the tissue of the intestinal wall after advancement.Retaining remembers 43 can be arranged in various patterns 43 p toenhance tissue retention such as two or more barbs symmetrically orotherwise distributed around and along member shaft 44 as is shown inthe embodiments of FIGS. 20a and 20b . Additionally, in manyembodiments, penetrating member will also include a recess or othermating feature 46 for attachment to a coupling component which attachesthe penetrating member to the balloon (such as advancement member 80 adescribed below).

As described above, tissue penetrating member 340 can be fabricated froma number of drugs and other therapeutic agents 3101. The penetratingmember may be fabricated entirely from drug 3101 or may have otherconstituent components as well, e.g., various pharmaceutical excipients.Typically, the drug or other therapeutic agent 3101 will be mixed inwith a biodegradable polymer 3105 such as PGLA, cellulose or otherbiodegradable material described herein or known in the art. In suchembodiments, the penetrating member 340 may comprise a substantiallyheterogeneous mixture of drug 3101 and biodegradable polymer 3105.Alternatively, the penetrating member may 340 include a 341 portionformed substantially from biodegradable material 3105 and a separatesection or compartment 342 that is formed from or contains drug 3101 asshown in the embodiment of FIG. 20 c.

Tissue penetrating member 340 can be fabricated using one or morepolymer and pharmaceutical fabrication techniques known in the art. Forexample, drug 3101 (with or without biodegradable material 3105) can bein solid form and then formed into the shape of the tissue penetratingmember 340 using molding, compaction or other like method with one ormore binding agents added. Alternatively, drug 3101 and/or drugpreparation 3100 may be in solid or liquid form and then added to thebiodegradable polymer 3105 in liquid form with the mixture then formedinto the penetrating member 340 using molding or other forming methodknown in the polymer arts.

Desirably, embodiments of the tissue penetrating member 340 comprising adrug or other therapeutic agent 3101 and degradable polymer 3105 areformed at temperatures which do not produce any substantial thermaldegradation of drug including drugs such as various peptides andproteins. This can be achieved through the use of room-temperaturecuring polymers and room temperature molding and solvent evaporationtechniques known in the art. In particular embodiments, the amount ofthermally degraded drug or other therapeutic agent within the tissuepenetrating member is desirably less than about 10% by weight and morepreferably, less than 5% and still more preferably less than 1%. Thethermal degradation temperature(s) for a particular drug are eitherknown or can be determined using methods known in the art and then thistemperature can be used to select and adjust the particular polymerprocessing methods (e.g., molding, curing. solvent evaporation methodsetc.) to minimize the temperatures and associated level of drug thermaldegradation.

Tissue penetrating member 340 is desirably configured to be detachablycoupled (directly or indirectly) to the balloon or other expandablemember 330 so that after advancement of the tissue penetrating member340 into the intestinal wall, the penetrating member detaches from theballoon. Detachability can be implemented by a variety of meansincluding: i) the configuration and strength of the joint betweenpenetrating member 340 and advancement member 380 a (or otherintermediary component(s) coupling member 340 to balloon 330); 2) theconfiguration and placement of tissue retaining features 343 onpenetrating member 340; and iii) the depth of penetration of shaft 344into the intestinal wall. Using one or more of these factors,penetrating member 340 be configured to detach as a result of balloondeflation (where the retaining features 343 hold the penetrating memberin tissue as the balloon deflates or otherwise pulls back away from theintestinal wall) and/or the forces exerted on capsule 320 by aperistaltic contraction of the small intestine.

Tissue penetrating member 340 can be directly or indirectly coupled toballoon 330. Referring now to FIGS. 21a-21b and 22, indirect couplingcan be implemented using one or more coupling components 380 such as anadvancement member 380 a. Accordingly, in particular embodiments, thetissue penetrating member 340 may be coupled to balloon 330 by anadvancement member 380 a comprising a rigid structure attached to theballoon surface 338 which detachably engages the penetrating member 340.The advancement member 380 a engages the penetrating member 340 by meansof an attachment feature 381 such as a pin or other protrusion 382(integral or attached to member 380 a) which fits into a recess or othermating feature 346 of the penetrating member as is shown in theembodiment of FIG. 21a . The pin 382 and recess 346 can be configured todetach from the force of balloon deflation and/or force applied tocapsule 320 by peristaltic contraction. In many embodiment, advancementmember 380 a can have a larger horizontal surface area 383 than thesurface area 347 of penetrating member 340 so as to function as a forceconcentration element 384 as is shown in the embodiment of FIG. 21b . Inuse force concentration element 384 functions to increase the force perunit area applied to the penetrating member from expansion of balloon330 or other expandable member.

In some embodiments, the advancement member 480 a can be coupled to theballoon 430 via a support member 486 as is shown in the embodiments ofFIGS. 22a and 22b . Support member 486 may correspond to a platform 486having one surface 487 attached to the balloon surface 438 and the othersurface 488 attached to the advancement member 480 a (one or both ofthese attachments can be an adhesive attachment) as is shown in theembodiment of FIG. 22a . Platform 486 is desirably rigid, can have aplate-like structure and can be sized to allow for attachment andadvancement of multiple advancement members 480 a and tissue penetratingmembers 440 at the same time as is shown in the embodiment of FIG. 22b .For example, in particular embodiments, three, four or five groups ofadvancement and tissue penetrating members can be attached to platform486, with additional numbers contemplated. In such embodiments, theplatform may include a recess 489 for positioning of isolation valve450.

Also, platforms 486 can be placed on either side of balloon 430 to allowfor bilateral deployment of tissue penetrating members 440 intointestinal wall IW as is shown in the embodiment of FIGS. 23a and 23b .In addition to delivering more drug, bilateral deployment serves toanchor capsule 420 on both sides of the intestinal wall IW duringdeployment of penetrating members 440, thus reducing the likelihood ofthe capsule from being dislodged during deployment (e.g., due toperistaltic contraction). In these and related embodiments tissuepenetrating members 440 can be directly coupled to platform 486 withoutnecessarily using advancement members 480 a. Desirably, both advancementmembers 480 and platform 486 are constructed from biodegradablematerials such as PGLA, which can be cross linked and/or copolymerizedwith to have increased rigidity to support the advancement ofpenetrating members 440 into tissue.

As an additional or alternative embodiment to the use of advancementmember 480 a and/or platform 468, tissue penetrating members 440 may bedirectly coupled to the balloon 430, e.g., by an adhesive where theadhesive force is less than the necessary to pull penetrating member outof tissue once it is deployed into the intestinal wall. In these andrelated embodiments, the tissue penetrating members 440 may also beconfigured to tear the balloon wall 432 when they detach from theballoon and thus provide a means for balloon deflation.

In various embodiments, penetrating members 440 can carry the same or adifferent drug 4101 or other therapeutic agent. The former configurationallows for the delivery of greater amounts of a particular drug 4101,while the later, allows two or more different drugs to be delivered intothe intestinal wall at about the same time to facilitate drug treatmentregimens requiring substantial concurrent delivery of multiple drugs.

In various embodiments, depending upon the drug and associated drugregimen (e.g., dose and times per day, etc), tissue penetrating members440 can be placed and distributed in a number of locations and patternson the balloon surface. As described above for the embodiments of FIGS.23a and 23b , tissue penetrating members 440 can be placed on oppositesides of balloon surface 438 so that balloon inflation can place tissuepenetrating members 440 on opposite sides of the intestinal wall IW.Referring now to FIGS. 24a-24b , in other embodiments, tissuepenetrating members 440 can be symmetrically or otherwise distributedaround substantially the entire perimeter 430 p of the balloon 430 orother expandable member 430 as is shown in the embodiments of FIGS. 24aand 24b . In use, such embodiments not only anchor capsule 420 into theintestinal wall IW (as described above for bidirectional deployment) butalso place tissue penetrating members 440 in a distributed pattern 440 paround the circumference of the intestinal wall IW. Embodiments of theinvention utilizing such a distributed delivery of drug into theintestinal wall can achieve the following: i) allow for additionalamounts of a particular drug to be delivered; and ii) provide for fasterabsorption of the drug into the blood stream due to a more evendistribution of the drug within the intestinal wall (e.g., due toplacement of the tissue penetrating members within a larger volume ofintestinal vascular for mass transfer and absorption into the blood).

As described herein, many embodiments of device 510 include a drugcarrying tissue penetrating member 540 as a means for delivering drug orother therapeutic agent 5101 into the intestinal wall. Referring now toFIGS. 25a-25b and 26, as an alternative or additional means fordelivering drug into the intestinal wall, in various embodiments, device510 can also be configured to inject drug 5101 into the intestinal wallby means of hollow tissue penetrating members 548 coupled to one or moredrug reservoirs 527. Hollow tissue penetrating members 548 include atleast one lumen 549. Reservoirs 527 are desirably compressible byexpansion of the balloon or other expandable member 530 and can thuscomprise various biodegradable elastic polymers. The reservoirs 527 cancontain drug or other therapeutic agent 5101 in liquid or powder form.For liquid form, the drug will be dissolved in an aqueous drug solution5104. In these and related embodiments, reservoirs 527 are fluidicallycoupled to hollow tissue penetrating members 548 such that inflation ofballoon 530 compresses the reservoirs 527 so as to force the drugsolution 5104 through tissue penetrating member lumen 549 and into theintestinal wall as is shown in FIGS. 25a and 25b . In these and relatedembodiments apertures 526, can include a guide tube 526 g, which ishorizontally aligned with the tip 544 of penetrating member 548 andconfigured to guide the advancement of penetrating member 548 out ofcapsule 520 and into the intestinal wall. Multiple reservoirs 527 arecontemplated including two, three, four or more. In particularembodiments, two reservoirs 527 can be coupled to a hollow tissuepenetrating member with the reservoirs placed about 180 degrees apartwith respect to penetrating member shaft 544. Typically, the reservoirs527 will be fluidically coupled to the hollow penetrating member 548 bymeans of a manifold 590. Suitable manifolds 590 include a t-shapedmanifold 590 t having connectors 592 on either of its lateral ends 593for connection to reservoirs 527 and a central connector 594 forconnection to hollow tissue penetrating member 547 and a central lumenor channel 595 going to all connectors 591 (FIG. 16). Other shapes andmanifold configurations are also contemplated, for example, Y-shaped(connecting two reservoirs to tissue penetrating member 548).

In some embodiments, balloon 30 or other expandable member 30 can beexpanded responsive to a sensor 67, such as a pH sensor 68 or otherchemical sensor which detects the presence of the capsule in the smallintestine. Sensor 67 (FIG. 1b ) can then send a signal to a controllableembodiment of isolation valve 50 or to an electronic controller 29 ccoupled to a controllable isolation valve 50 to open and thus expandballoon 30 as is described herein. Embodiments of a pH sensor 68 cancomprise an electrode-based sensor or it can be a mechanically-basedsensor such as a polymer which shrinks or expands upon exposure to aselected pH or other chemical conditions in the small intestine. Inrelated embodiments, an expandable/contractable sensor 67 can alsocomprise the actuating mechanism 60 itself by using the mechanicalmotion from the expansion or contraction of the sensor.

Referring now to FIGS. 27a-27b and 28a-28b , in related embodiments, anexpandable/contractible pH sensor 668 can also comprise the isolationvalve 650 itself, by configuring the sensor to expand or contract so asto open a channel between balloon compartments 634 and 635. According toone embodiment for such an approach, a pH sensor 668 may be integratedinto a collar valve 655 where sensor 668 comprises all or a portion of acollar 655 c that is placed over connecting portion 636 of balloon 630(FIGS. 27a and 27b ). In this embodiment, sensor 668 would be anexpandable sensor 668 e, configured to expand upon exposure to the pHconditions in the small intestine (e.g., a pH above 6.0, 6.5, 7.0, 7.1,7.2, etc) so as to either have the collar come off or significantlyloosen collar 655 c enough to allow contents of compartments 634 and 635to mix. According to another embodiment shown in FIGS. 28a and 28b , apH sensor 668 could be integrated into a beam valve 658 describedherein, where the beam is under compressive load by being snap fitagainst the capsule interior surface 624. The beam applies a portion ofthis compressive load onto balloon connecting section 636 so as tomaintain the seal between compartments 634 and 635. In this case, sensor668 would be a contractible sensor 668 c configured to open valve 650 bycontracting upon exposure to higher pH in the intestine, so that thebeam shortens sufficiently so that it falls out of place against capsulesurface 624 or other wise no longer applies a compressive loadsufficient to maintain a seal over balloon connecting section 636.

According to another embodiment for detecting when the device is in thesmall intestine (or other location in the GI tract), sensor 67 cancomprise pressure/force sensor such as strain gauge for detecting thenumber of peristaltic contractions that capsule 20 is being subject towithin a particular location in the intestinal tract (in suchembodiments capsule 20 is desirably sized to be gripped by the smallintestine during a peristaltic contraction). Different locations withinthe GI tract have different number of peristaltic contractions. Thesmall intestine has between 12 to 9 contractions per minute with thefrequency decreasing down the length of the intestine. Thus, accordingto one or more embodiments, detection of the number of peristalticcontractions can be used to not only determine if capsule 20 is in thesmall intestine, but the relative location within the intestine as well.In use, these and related embodiments allow for release of medication100 at a particular location in the small intestine.

As an alternative or supplement to internally activated drug delivery(e.g., using a release element and/or sensor), in some embodiments, theuser may externally send a signal to expand balloon 30 or otherexpandable member 30 to activate the actuating mechanism 60 to delivermedication 100 by means of RF, magnetic or other wireless signalingmeans known in the art. In various embodiments, including those withreference to FIG. 1b , external activation can be achieved by use of acontrollable isolation valve 50 for example, a radio frequency (RF)controlled miniature solenoid valve or other electro-mechanical controlvalve (not shown). In other embodiments, a controllable isolation valve50 may correspond to a miniature magnetically valve such as amagnetically controlled miniature reed switch (not shown). Suchelectromechanical or magnetic-based valves can be fabricated using MEMSand other micro-manufacturing methods. In these and related embodiments,the user can use a handheld communication device 13 (e.g., a hand heldRF device such as a cell phone) as is shown in the embodiment of FIG. 1b, to send a receive signals 17 from device 10. In such embodiments,swallowable device may include a transmitter 28 such as an RFtransceiver chip or other like communication device/circuitry. Handhelddevice 13 may not only includes signaling means, but also means forinforming the user when device 10 is in the small intestine or otherlocation in the GI tract. The later embodiment can be implementedthrough the use of logic resources 29 (e.g., a processor 29) coupled totransmitter 28 to signal to detect and singe to the user when the deviceis in the small intestine or other location (e.g., by signaling an inputfrom the sensor). Logic resources 29 may include a controller 29 c(either in hardware or software) to control one or more aspects of theprocess. The same handheld device can also be configured to alert theuser when balloon 30 or actuating mechanism 60 has been expanded oractivated (respectively) and the selected medication 100 delivered(e.g., using processor 29 and transmitter 28). In this way, the user isprovided confirmation that medication 100 has been delivered. Thisallows the user to take other appropriate drugs/therapeutic agents aswell as make other related decisions (e.g., for diabetics to eat a mealor not and what foods should be eaten). The handheld device can also beconfigured to send a signal to swallowable device 10 to over-rideisolation valve 50 or actuating mechanism 60 and so prevent delay oraccelerate the delivery of medication 100. In use, such embodimentsallow the user to intervene to prevent, delay or accelerate the deliveryof medication, based upon other symptoms and/or patient actions (e.g.,eating a meal, deciding to go to sleep, exercise etc). The user may alsoexternally expand balloon 30 or activate actuating mechanism 60 at aselected time period after swallowing the capsule. The time period canbe correlated to a typical transit time or range of transit times forfood moving through the user's GI tract to a particular location in thetract such as the small intestine.

Referring now to FIGS. 29a-29b and 30, in various embodiments, thecapsule 720 can include seams 722 of biodegradable material whichcontrollably degrade to produce capsule pieces 723 of a selectable sizeand shape to facilitate passage through the GI tract as is shown in theembodiment of FIGS. 11, 29 a and 29 b, for example. Seams 722 can alsoinclude pores or other openings 722 p for ingress of fluids into theseam to accelerate biodegradation as is shown in the embodiment of FIG.10. Other means for accelerating biodegradation of seams 722 can includepre-stressing the seam and/or including perforations 722 f in the seam(FIG. 10). In still other embodiments, seam 722 can be constructed ofmaterials and/or have a structure which is readily degraded byabsorption of ultrasound energy, e.g. high frequency ultrasound (HIFU),allowing the capsule to be degraded into smaller pieces using externallyor endoscopically (or other minimally invasive method) administeredultrasound.

Referring now to FIGS. 29a-29b and 30, in many embodiments seams 722 canalso be configured and arranged so as to allow capsule 720 to be brokeninto smaller pieces by the inflation of balloon 730 or other expandablemember 730. In particular embodiments, seams 722 can be oriented withrespect to capsule radial perimeter 721, including having a radialpattern 722 rp so as to have the capsule break into halves or otherfractional pieces along its perimeter. Seams 722 may also belongitudinally-oriented with respect to capsule lateral access 720 la tohave the capsule break up into lengthwise pieces.

As alternative or additional approach for breaking up capsule 720 byballoon inflation (or expansion of other expandable member 730), capsule720 can be fabricated from two or more separate joinable pieces 723 j(e.g., radial halves) that are joined at a joint 722 j formed by seams722 (which function as an adhesive joint) as shown in the embodiment ofFIG. 30. Alternatively, joinable pieces 723 j may be merely joined by amechanical fit such as a snap or press fit.

Suitable materials for seams 722 can include one or more biodegradablematerials described herein such as PGLA, glycolic acid etc. Seams 722can be attached to capsule body 720 using various joining methods knownin the polymer arts such as molding, hot melt junctions, etc.Additionally for embodiments of capsule 720 which are also fabricatedfrom biodegradable materials, faster biodegradation of seam 722 can beachieved by one or more of the following: i) fabricating the seam from afaster biodegrading material, ii) pre-stressing the seam, or iii)perforating the seam. The concept of using biodegradable seams 722 toproduce controlled degradation of a swallowable device in the GI tractcan also be applied to other swallowable devices such as swallowablecameras (or other swallowable imaging device) to facilitate passagethrough the GI tract and reduce the likelihood of such a device becomingstuck in the GI tract. Accordingly, embodiments of biodegradable seam722 can be adapted for swallowable imaging and other swallowabledevices.

In still other embodiments, seam 722 can be constructed of materialsand/or have a structure which is readily degraded by absorption ofultrasound energy, e.g. high frequency ultrasound (HIFU), allowing thecapsule to be degraded into smaller pieces using externally orendoscopically (or other minimally invasive method) administeredultrasound.

Another aspect of the invention provides methods for the delivery ofdrugs and other therapeutic agents (in the form of medication 100) intothe walls of the GI tract using one or more embodiments of swallowabledrug delivery device 10. An exemplary embodiment of such a method willnow be described. The described embodiment of drug delivery occurs inthe small intestine SI. However, it should be appreciated that this isexemplary and that embodiments of the invention can be used fordelivering drug in a number of locations in the GI tract including thestomach and the large intestine. For ease of discussion, the swallowabledrug delivery device 10 will sometimes be referred to herein as acapsule. As described above, in various embodiments device 10 may bepackaged as a kit 11 within sealed packaging 12 that includes device 10and a set of instructions for use 15. If the patient is using a handhelddevice 13, the patient may instructed to enter data into device 13either manually or via a bar code 18 (or other identifying indicia 18)located on the instructions 15 or packaging 12. If a bar code is used,the patient would scan the bar code using a bar code reader 19 on device13. After opening packaging 12, reading the instructions 15 and enteringany required data, the patient swallows an embodiment of the swallowabledrug delivery device 10. Depending upon the drug, the patient may takethe device 10 in conjunction with a meal (before, during or after) or aphysiological measurement such as a blood glucose measurement. Capsule20 is sized to pass through the GI tract and travels through thepatient's stomach S and into the small intestine SI through peristalticaction as is shown in the embodiment of FIG. 11. Once the capsule 10 isin the small intestine, the release element 70 is degraded by the basicpH in the small intestine (or other chemical or physical conditionunique to the small intestine) so as expand balloon 30 or otherexpandable member 30, actuate the actuating mechanism 60 and delivermedication 100 into the wall of the small intestine SI according to oneor more embodiments of the invention. For embodiments including a hollowneedle or other hollow tissue penetrating member 40, medication deliveryis effectuated by using balloon 30 the actuating mechanism 60 to advancethe needle 40 a selected distance into the mucosa of the intestinal wallIS, and then the medication is injected through the needle lumen byadvancement of the delivery member 50. The delivery member 50 iswithdrawn and the needle 40 is then withdrawn back within the body ofthe capsule (e.g. by recoil) detaching from the intestinal wall. Forembodiments of device 10 having multiple needles, a second or thirdneedle 42, 43 can also be used to deliver additional doses of the samedrug or separate drugs 101. Needle advancement can be done substantiallysimultaneously or in sequence. In preferred embodiments that usemultiple needles, needle advancement can be done substantiallysimultaneously so as to anchor device 10 in the small intestine duringdrug delivery.

After medication delivery, device 10 then passes through the intestinaltract including the large intestine LI and is ultimately excreted. Forembodiments having a tearable capsule, the capsule may immediately bebroken into smaller pieces by inflation of balloon 30. For embodimentsof the capsule 20 having biodegradable seams 22 or other biodegradableportions, the capsule is degraded in the intestinal tract into smallerpieces, to facilitate passage through and excretion from the intestinaltract as is shown in the embodiments of FIGS. 9a and 9b . In particularembodiments having biodegradable tissue penetrating needles/members 40,should the needle get stuck in the intestinal wall, the needlebiodegrades releasing the capsule 20 from the wall.

For embodiments of device 10 including a sensor 67, can be effectuatedby the sensor sending a signal to a controllable embodiment of isolationvalve 50 or actuating mechanism 60 and/or a processor 29/controller 29 ccoupled to the isolation valve 50 or actuating mechanism. Forembodiments of device 10 including external actuation capability, theuser may externally expand balloon 30 or activate actuating mechanism 60at a selected time period after swallowing the capsule. The time periodcan be correlated to a typical transit time or range of transit timesfor food moving through the user's GI tract to a particular location inthe tract such as the small intestine.

One or more embodiments of the above methods can be used for thedelivery of preparations 100 containing therapeutically effectiveamounts of a variety of drugs and other therapeutic agents 101 to treata variety of diseases and conditions. These include a number of largemolecule peptides and proteins which would otherwise require injectionand/or IV infusion due to chemical breakdown or other degradation of thecompound by the digestive fluids in the stomach and/or the lumen of thesmall intestine. Such compounds which can be delivered with variousembodiments of the invention can include without limitation, parathyroidhormones, growth hormones (e.g., IFG and other growth factors), insulincompounds, antibodies and other gamma globulin proteins (e.g., gammaglobulin) interferons and other cytokines, glucagon like peptides e.g.,(GLP-1, exenatide) and other incretins, chemotherapeutic agents(doxorubicin) and other like compounds. Embodiments of the inventionallow these and other compounds to be delivered into the wall of thesmall intestine and subsequently absorbed into the blood stream withminimal or no loss of activity of the compound, e.g., in the case of anantibody, minimal or no loss in affinity and/or specificity to a targetantigen; in the case of an interferon or other cytokine, minimal or noloss in an immune stimulating effect, in the case of insulin or GLP-1,minimal or no loss in glucose regulating ability; in the case of growthhormone, minimal or no loss in growth stimulating effect; in the case ofa chemotherapeutic agent for the treatment of cancer, minimal or no lossin cancer treatment effect (e.g., a tumor necrosis, and/or reduced celldivision); and in the case of any polypeptide, minimal or no loss inaffinity and/or specificity to a target binding site. Suitable drugs andother therapeutic agents which can be delivered by embodiments of theinvention include any number of orally delivered agents, antibiotics(vancomycin, penicillin, erythromycin, etc.), antivirals (proteaseinhibitors, anti-seizure compounds (fluosemide, dilatin), non-steroidalanti-inflamatory drugs (NSAIDS) such as ibuprofen), variouschemotherapeutic agents (e.g., interferon), antibiotics, antivirals,insulin and related compounds, glucagon like peptides (e.g., GLP-1,exenatide), parathyroid hormones, growth hormones (e.g., IFG and othergrowth factors), anti-seizure agents (e.g., furosimide), anti-migrainemedication (sumatriptan), immune suppression agents (e.g., cyclosporine)and anti-parasitic agents such as various anti-malarial agents. Thedosage of the particular drug can be titrated for the patient's weight,age or other parameter. Embodiments of the invention also allow dosagesof drug other therapeutic agent 101 to be advantageously adjusted forother factors as well. For example, for drugs that would otherwise bepartially degraded or poorly absorbed in the GI tract, the amount ordose of drug 101 to achieve a desired or therapeutic effect (e.g.,insulin for blood glucose regulation, furosimide for anti-seizure) canbe less than the amount required should the drug have been delivered byconventional oral delivery (e.g., a swallowable pill that is digested inthe stomach and absorbed through the wall of the small intestine). Thisis due to the fact that there is little or no degradation of the drug byacid and other digestive fluids in the stomach and the fact that all, asopposed to only a portion of the drug is delivered into the wall of thesmall intestine (or other lumen in the intestinal tract, e.g., largeintestine, stomach, etc.). Depending upon the drug 101, the dose 102delivered in preparation 100 can be in the range from 100 to 5% of adose delivered by conventional oral delivery means (e.g., a formulatedpill) to achieve a desired therapeutic effect (e.g., blood glucoseregulation, seizure regulation, etc.) with even lower amountscontemplated. The particular dose reduction can be titrated based uponthe particular drug, the condition to be treated, and the patient'sweight, age and condition. For some drugs (with known levels ofdegradation in the intestinal tract) a standard dose reduction can beemployed (e.g., 10 to 20%). Larger amounts of dose reduction can be usedfor drugs which are more prone to degradation in the GI tract and poorabsorption. In this way, the potential toxicity (particularly to nontarget tissue sites) and other deleterious side effects (e.g., gastriccramping, diarrhea, irritable bowel, hemorrhage, etc.) of a particulardrug or drugs delivered by device 10 can be reduced because the ingesteddose is lowered and all or nearly all of the drug is delivered into thewall of the small intestine. This in turn, improves patient compliancebecause the patient has a reduction both in the severity and incidenceof deleterious effects. Additional benefits of embodiments employ dosereduction of drug 101 that include a reduced likelihood for the patientto develop a tolerance to the drug (requiring higher doses) and, in thecase of antibiotics or antivirals, for the patient to develop resistantstrains of bacteria or viruses (e.g., resistance to the use ofvancomycin by bacteria or to a protease inhibitor by the Aids virus).For the case of a chemotherapeutic agent for the treatment of cancer,the deleterious effect can comprise the development of resistance to thechemotherapeutic agent by cancer cells as well as toxicity to non-targettissue. For the case of an anti-seizure medication such as dilatin, thedeleterious effects can include various neuromuscular conditions such astremor, nystagmus, slurred speech, dizziness, memory and concentrationproblems as well conditions such as rash and bone loss. For anti-seizureand/or diuretics such as furesomide such deleterious effects can includevarious neuromuscular, vascular, gastro intestinal effects such asdizziness, low blood pressure, dehydration, nausea, loss ofelectrolytes, tinnitus and rash. Also, other levels of dose reductioncan be achieved for patients who have undergone gastric bypass surgeryand other procedures in which sections of the small intestine have beenremoved or its working (e.g., digestive) length otherwise effectivelyshortened. In these and related embodiments, levels of dose reductioncan be achieved in the range of 25 to 50% or even greater and thepatient need only take one dose of the drug versus multiple dosesbecause of poor absorption issues. In still other embodiments, the doseof a particular orally delivered drug 101 can be increased because thevarious deleterious effects in the GI system (e.g., cramping, bleeding,etc.) are avoided since the drug or other therapeutic agent is injecteddirectly into the wall of the small intestine. This increased dosage inturn allows for one or more of the following: fewer doses, fastertreatment, faster obtainment of a therapeutic effective level of thedrug in the blood stream, better control of blood concentrations andother pharmacokinetic parameters. In various embodiments, the dosage ofa particular drug can increased in the range of 5 to 100% or higher. Theamount of the increase can again be titrated based on the patient's,weight, age, condition and individual tolerance to the drug (which canbe determined e.g., by using various biomarkers of tolerance and/ortoxicity).

In addition to delivery of a single drug, embodiments of swallowabledrug delivery device 10 and its methods of their use can be used todeliver a plurality of drugs for the treatment of multiple conditions orfor the treatment of a particular condition (e.g., protease inhibitorsfor treatment HIV AIDS). In use, such embodiments allow a patient toforgo the necessity of having to take multiple medications for aparticular condition or conditions. Also, they provide a means forfacilitating that a regimen of two or more drugs is delivered andabsorbed into the small intestine and thus, the blood stream, at aboutthe same time. Due to difference in chemical makeup, molecular weight,etc, drugs can be absorbed through the intestinal wall at differentrates, resulting in different pharmacokinetic distribution curves.Embodiments of the invention address this issue by injecting the desireddrug mixtures at substantially the same time. This in turn, improves thepharmacokinetics and thus the efficacy of the selected mixture of drugs.Additionally, eliminating the need to take multiple drugs isparticularly beneficial to patients who have one or more long termchronic conditions including those who have impaired cognitive orphysical abilities.

In various applications, embodiments of the above methods can be used todeliver preparations 100 including drugs and therapeutic agents 101 toprovide treatment for a number of medical conditions and diseases. Themedical conditions and diseases which can be treated with embodiments ofthe invention can include without limitation: cancer, hormonalconditions (e.g., hypo/hyper thyroid, growth hormone conditions),osteoporosis, high blood pressure, elevated cholesterol andtriglyceride, diabetes and other glucose regulation disorders, infection(local or septicemia), epilepsy and other seizure disorders,osteoporosis, coronary arrhythmia's (both atrial and ventricular),coronary ischemia anemia or other like condition. Still other conditionsand diseases are also contemplated.

In many embodiments, the treatment of the particular disease orcondition can be performed without the need for injecting the drug orother therapeutic agent (or other non-oral form of delivery such assuppositories) but instead, relying solely on the therapeutic agent(s)that is delivered into the wall of the small intestine or other portionof the GI tract. For example, diabetes or another glucose regulationdisorder can be treated (e.g., by controlling blood glucose levels)solely through the use of insulin that is delivered into the wall of thesmall intestine without the need for the patient to ever inject insulin.Similarly, the patient need not take conventional oral forms of a drugor other therapeutic agent, but again rely solely on delivery into thewall of the small intestine using embodiments of the swallowablecapsule. In other embodiments, the therapeutic agent(s) delivered intothe wall of the small intestine can be delivered in conjunction with aninjected dose of the agent(s). For example, the patient may take a dailydose of insulin or compound for blood glucose regulation using theembodiments of the swallowable capsule, but only need take an injecteddose every several days or when the patient's condition requires it(e.g., hyperglycemia). The same is true for therapeutic agents that aretraditionally delivered in oral form (e.g., the patient can take theswallowable capsule and take the conventional oral form of the agent asneeded). The dosages delivered in such embodiments (e.g., the swallowedand injected dose) can be titrated as needed (e.g., using standard doseresponse curve and other pharmacokinetic methods can be used todetermine the appropriate dosages). Also, for embodiments usingtherapeutic agents that can be delivered by conventional oral means, thedose delivered using embodiments of the swallowable capsule can betitrated below the dosage normally given for oral delivery of the agentsince there is little or no degradation of the agent within the stomachor other portion of the intestinal tract (herein again standard doseresponse curve and other pharmacokinetic methods can be applied).

Various groups of embodiments of preparation 100 containing one or moredrugs or other therapeutic agents 101 for the treatment of variousdiseases and conditions will now be described with references todosages. It should be appreciated that these embodiments, including theparticular therapeutic agents and the respective dosages are exemplaryand the preparation 100 can comprise a number of other therapeuticagents described herein (as well as those known in the art) that areconfigured for delivery into a luminal wall in the intestinal tract(e.g., the small intestinal wall) using various embodiments of device10. The dosages can be larger or smaller than those described and can beadjusted using one or more methods described herein or known in the art.In one group of embodiments, therapeutic agent preparation 100 cancomprise a therapeutically effective dose of insulin for the treatmentof diabetes and other glucose regulation disorders. The insulin can behuman or synthetically derived as is known in the art. In oneembodiment, preparation 100 can contain a therapeutically effectiveamount of insulin in the range of about 1-10 units (one unit being thebiological equivalent of about 45.5 μg of pure crystalline insulin),with particular ranges of 2-4, 3-9, 4-9, 5-8 or 6-7. The amount ofinsulin in the preparation can be titrated based upon one or more of thefollowing factors (herein, then “glucose control titration factors”): i)the patient's condition (e.g., type 1 vs. type II diabetes; ii) thepatients previous overall level of glycemic control; iii) the patient'sweight; iv) the patient's age; v) the frequency of dosage (e.g., oncevs. multiple times a day); vi) time of day (e.g., morning vs. evening);vii) particular meal (breakfast vs. dinner); viii) content/glycemicindex of a particular meal (e.g., meals having a high fat/lipid andsugar content (which tend to cause a rapid rise in blood sugar and thushave a higher glycemic index) vs. low fat and sugar content that do not(and thus have a lower glycemic index)); and ix) content of thepatient's overall diet (e.g., amount of sugars and other carbohydrates,lipids and protein consumed daily).

In another group of embodiments, therapeutic agent preparation 100 cancomprise a therapeutically effective dose of one or more incretins forthe treatment of diabetes and other glucose regulation disorders. Suchincretins can include Glucacon like peptides 1 (GLP-1) and theiranalogues, and Gastric inhibitory peptide (GIP). Suitable GLP-1analogues include exenatide, liraglutide, albiglutide and taspoglutideas well as their analogues, derivatives and other functionalequivalents. In one embodiment preparation 100 can contain atherapeutically effective amount of exenatide in the range of about 1-10μg, with particular ranges of 2-4, 4-6, 4-8 and 8-10 μg respectively. Inanother embodiment, preparation 100 can contain a therapeuticallyeffective amount of liraglutide in the range of about 1-2 mg(milligrams), with particular ranges of 1.0 to 1.4, 1.2 to 1.6 and 1.2to 1.8 mg respectively. One or more of the glucose control titrationfactors can be applied to titrate the dose ranges for exenatide,liraglutide or other GLP-1 analogue or incretin.

In yet another group of embodiments, therapeutic agent preparation 100can comprise a combination of therapeutic agents for the treatment ofdiabetes and other glucose regulation disorders. Embodiments of such acombination can include therapeutically effective doses of incretin andbiguanide compounds. The incretin can comprise one or more GLP-1analogues described herein, such as exenatide and the biguanide cancomprise metformin (e.g., that available under the Trademark ofGLUCOPHAGE® manufactured by Merck Sante S.A.S.) and its analogues,derivatives and other functional equivalents. In one embodiment,preparation 100 can comprise a combination of a therapeuticallyeffective amount of exenatide in the range of about 1-10 .mu.g and atherapeutically effective amount of metformin in a range of about 1 to 3grams. Smaller and larger ranges are also contemplated with one or moreof the glucose control titration factors used to titrate the respectivedose of exenatide (or other incretin) and metformin or other biguanide.Additionally, the dosages of the exenatide or other incretin andmetformin or other biguanide can be matched to improve the level ofglucose control for the patient (e.g., maintenance of blood glucosewithin normal physiological levels and/or a reduction in the incidenceand severity of instances of hyperglycemia and/or hypoglycemia) forextended periods of time ranging from hours (e.g., 12) to a day tomultiple days, with still longer periods contemplated. Matching ofdosages can also be achieved by use of the glucose control regulationfactors as well as monitoring of the patient's blood glucose levels forextended periods using glycosylated hemoglobin (known as hemoglobin Alc,HbAlc, AlC, or Hblc) and other analytes and measurements correlative tolong term average blood glucose levels.

In still yet another group of embodiments, therapeutic agent preparation100 can comprise a therapeutically effective dose of growth hormone forthe treatment of one or more growth disorders, as well as wound healing.In one embodiment, preparation 100 can contain a therapeuticallyeffective amount of growth hormone in the range of about 0.1-4 mg, withparticular ranges of 0.1-1, 1-4, 1-2 and 2-4, with still larger rangescontemplated. The particular dose can be titrated based on one or moreof the following: i) the particular condition to be treated and itsseverity (e.g., stunted growth, vs. wound healing); ii) the patient'sweight; iii) the patient's age; and iv) the frequency of dosage (e.g.,daily vs. twice daily).

In still yet another group of embodiments, therapeutic agent preparation100 can comprise a therapeutically effective dose of parathyroid hormonefor the treatment osteoporosis or a thyroid disorder. In one embodiment,preparation 100 can contain a therapeutically effective amount ofparathyroid hormone in the range of about 1-40 μg with particular rangesof 10-20, 20-30, 30-40 and 10-40 μg, with still larger rangescontemplated. The particular dose can be titrated based on one or moreof the following: i) the particular condition to be treated and itsseverity (e.g., the degree of osteoporosis as determined by bone densitymeasurements); ii) the patient's weight; iii) the patient's age; and iv)the frequency of dosage (e.g., daily vs. twice daily).

The foregoing description of various embodiments of the invention hasbeen presented for purposes of illustration and description. It is notintended to limit the invention to the precise forms disclosed. Manymodifications, variations and refinements will be apparent topractitioners skilled in the art. For example, embodiments of the devicecan be sized and otherwise adapted for various pediatric and neonatalapplications as well as various veterinary applications. Also thoseskilled in the art will recognize, or be able to ascertain using no morethan routine experimentation, numerous equivalents to the specificdevices and methods described herein. Such equivalents are considered tobe within the scope of the present invention and are covered by theappended claims below.

Elements, characteristics, or acts from one embodiment can be readilyrecombined or substituted with one or more elements, characteristics oracts from other embodiments to form numerous additional embodimentswithin the scope of the invention. Moreover, elements that are shown ordescribed as being combined with other elements, can, in variousembodiments, exist as standalone elements. Hence, the scope of thepresent invention is not limited to the specifics of the describedembodiments, but is instead limited solely by the appended claims.

What is claimed is:
 1. A swallowable device for delivering a therapeuticagent preparation into an intestinal wall of a patient's intestinaltract, the device comprising: a swallowable capsule sized to passthrough the intestinal tract; a reservoir disposed in the capsule, thereservoir containing the therapeutic agent preparation comprising atherapeutic agent; a needle fluidically coupled to the reservoir; theneedle having a lumen and engagable with the intestinal wall; a releaseelement operably coupled to at least one of the reservoir or the needle,the release element configured to cause release of the therapeutic agentpreparation from the reservoir through the lumen and into the intestinalwall, responsive to a condition in the small intestine; and an actuatorcoupled to the release element, the actuator configured to apply forceto the reservoir to drive the therapeutic agent preparation from thereservoir through the lumen and into the intestinal wall, wherein theactuator comprises an expandable member disposed within the capsule in apartially non-expanded shape, the expandable member including a firstportion and a second portion, the first portion including a liquid, thesecond portion including a reactant configured to react with the liquidto expand the expandable member, wherein the first and second portionsof the expandable member are separated by a separation valve which isconfigured to degrade upon exposure to a selected pH in the smallintestine, and wherein the expandable member is configured to expand toapply force to the reservoir to drive the therapeutic agent preparationtherefrom in response to the liquid from the first portion mixing withthe reactant in the second portion.
 2. The device of claim 1, whereinthe release element is further configured to retain the needle withinthe capsule during transit of the capsule through portions of theintestinal tract and to release the needle into the intestinal wallresponsive to said condition in the small intestine.
 3. The device ofclaim 1, wherein the condition is a selected pH in the small intestine.4. The device of claim 3, wherein the selected pH is greater than about7.4.
 5. The device of claim 1, wherein the release element comprises abiodegradable material.
 6. The device of claim 1, wherein the releaseelement is positioned on a surface of the swallowable capsule.
 7. Thedevice of claim 1, wherein the release element comprises a plug or apatch positioned on a surface of the capsule.
 8. The device of claim 1,wherein the expandable member comprises an expandable balloon.
 9. Thedevice of claim 1, wherein the actuator causes the needle to engage withthe intestinal wall.
 10. The device of claim 1, wherein the therapeuticagent comprises insulin for treatment of diabetes or a glucoseregulation disorder.
 11. The device of claim 1, wherein the therapeuticagent comprises an incretin for treatment of diabetes or a glucoseregulation disorder.
 12. The device of claim 11, wherein the incretincomprises a glucagon-like peptide-1 (GLP-1), a GLP-1 analogue,exenatide, liraglutide, albiglutide, taspoglutide or a gastricinhibitory polypeptide (GIP).
 13. The device of claim 1, wherein thetherapeutic agent preparation comprises an additional therapeutic agent,wherein the therapeutic agent and the additional therapeutic agent forma combination of therapeutic agents for treatment of diabetes or aglucose regulation disorder.
 14. The device of claim 13, wherein thecombination comprises an incretin and an biguanide.
 15. The device ofclaim 14, wherein the incretin comprises exenatide and the biguanidecomprises metformin.
 16. The device of claim 1, wherein the therapeuticagent comprises growth hormone.
 17. The device of claim 1, wherein thetherapeutic agent comprises parathyroid hormone for treatment ofosteoporosis or a thyroid disorder.
 18. The device of claim 1, whereinthe therapeutic agent comprises a protein or a polypeptide.
 19. Thedevice of claim 18, wherein the protein or the polypeptide comprises agamma globulin or an antibody.
 20. The device of claim 1, wherein thereactant from the second portion of the expandable member is configuredto react with the liquid from the first portion of the expandable memberto produce a gas which expands the expandable member to apply force tothe reservoir to drive the therapeutic agent preparation therefrom. 21.The device of claim 1, wherein the reactant in the second portioncomprises one or more of an acid or a base.
 22. The device of claim 21,wherein the acid comprises citric acid and the base comprises sodiumhydroxide.